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    Summary
    EudraCT Number:2017-000070-11
    Sponsor's Protocol Code Number:MK-6072-001
    National Competent Authority:Norway - NOMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-09-05
    Trial results View 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 ConcernedNorway - NOMA
    A.2EudraCT number2017-000070-11
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of a Single Infusion of Bezlotoxumab (MK 6072, Human Monoclonal Antibody to C. difficile Toxin B) in Children Aged 1 to <18 Years Receiving Antibacterial Drug Treatment for C. difficile Infection (MODIFY III)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The study of Bezlotoxumab (MK-6072) versus placebo in children with Clostridium Difficile (CDI) diarrhea
    A.3.2Name or abbreviated title of the trial where available
    Bezlotoxumab (MK-6072) versus placebo in children with CDI: MODIFY III
    A.4.1Sponsor's protocol code numberMK-6072-001
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/340/2014
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 (Bezlotoxumab)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBEZLOTOXUMAB
    D.3.9.2Current sponsor codeMK-6072
    D.3.9.3Other descriptive nameBEZLOTOXUMAB
    D.3.9.4EV Substance CodeSUB127968
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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) Yes
    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
    Prevention of recurrent Clostridium difficile infection (CDI)
    E.1.1.1Medical condition in easily understood language
    Diarhhea caused by Clostridium 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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10012748
    E.1.2Term Diarrhoea, Clostridium difficile
    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
    1. To characterize bezlotoxumab PK in 2 age cohorts (Age Cohort 1: 12 to <18 years; Age Cohort 2: 1 to <12 years) of pediatric participants to support dose selection in this population.
    2.To evaluate the safety and tolerability of a single infusion of bezlotoxumab as compared with a single infusion of placebo through 12 weeks following infusion.
    E.2.2Secondary objectives of the trial
    1. To estimate the proportion of participants who have a CDI recurrence within 12 weeks following administration of a single infusion of bezlotoxumab or placebo.
    2. To estimate the proportion of participants with sustained clinical response over a period of 12 weeks in participants who received a single infusion of bezlotoxumab or placebo.
    3. To estimate efficacy (CDI recurrence and sustained clinical response) in the subset of participants at high risk of CDI recurrence within 12 weeks following administration of a single infusion of bezlotoxumab or placebo.
    4. To assess the incidence of infusion-related reactions in participants who received a single infusion of bezlotoxumab or placebo.
    5. To assess the potential for bezlotoxumab to induce immunogenicity within 12 weeks following administration of a single infusion of bezlotoxumab.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Merck will conduct Future Biomedical Research on DNA (Blood, serum/plasma and stool) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.
    E.3Principal inclusion criteria
    1. At the time of screening, participant
    A) has suspected or confirmed CDI, as evidenced by the following: 1. had a change in normal bowel habits for 2 or more calendar days with either watery diarrhea (for participants using diapers or other type of fecal collection device, Bristol Stool Scale types 6 or 7) or at least 6 UBMs (eg, takes shape of container, or Bristol Stool Scale types 5, 6, or 7) within a 48-hour period, and 2.produced a stool sample that has tested positive for toxigenic C. difficile according to local diagnostic criteria.
    B) is receiving or is planning to receive a 10- to 21-day course of antibacterial drug treatment for CDI, which is defined as oral vancomycin, oral metronidazole, or oral fidaxomicin. Additionally, IV metronidazole may be given concurrently with oral vancomycin or oral fidaxomicin
    2. At the time of randomization/study infusion, participant: a)has a diagnosis of CDI confirmed by a diagnostic assay which detects the presence of C. difficile toxin in stool and b)is still receiving antibacterial drug treatment for CDI
    3.Participant is of either sex and of any race, and ≥1 year to <18 years of age at the time of randomization
    4. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a)Not a woman of childbearing potential (WOCBP) as defined in the protocol OR b) A WOCBP who agrees to use any contraceptive method listed in the protocol from Day 1 through at least 12 weeks after the single infusion of study treatment.
    5. The participant (or legally acceptable representative [LAR] if applicable) provides written informed consent/assent for the trial. The participant or LAR may also provide consent/assent for Future Biomedical Research (FBR). However the participant may participate in the main trial without participating in FBR
    6. Participant must be able to adhere to the study visit schedules
    7. Participant and/or parent or caregiver must be able to read, understand, and complete the daily diary
    E.4Principal exclusion criteria
    1. Participant has an uncontrolled chronic diarrheal illness such as, but not limited to, Crohn’s disease, ulcerative colitis, or with a condition such that their normal 24-hour bowel movement habit is 3 or more UBMs. Participants with a history of IBD who are controlled (ie, had no recent active diarrhea/UBMs prior to current CDI episode) may be enrolled if in the opinion of the investigator, the symptoms are more likely due to CDI than a flare of the IBD
    2. Has a known hypersensitivity to bezlotoxumab, its active substance and/or any of its excipients
    3. Participant for whom, at the time of randomization, the planned course of antibacterial drug treatment for CDI is longer than 21 days
    4. Participant has received any treatment or procedure listed in the protocol within the indicated exclusion window
    5. Participant has previously participated in this trial, has previously received bezlotoxumab, has received an experimental mAb against C. difficile toxin B, or has received a vaccine directed against C. difficile or its toxins
    6. Participant has received an investigational trial agent within the previous 30 days, or is currently participating in or scheduled to participate in any other clinical trial with an investigational agent during the 12-week trial period
    7. Participant is not expected to survive for 72 hours
    8. Participant has any other condition that, in the opinion of the investigator, would jeopardize the safety or rights of the participant, would make it unlikely for the participant to complete the trial, or would confound the results of the trial
    9. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial
    E.5 End points
    E.5.1Primary end point(s)
    1. Pharmacokinetic: The AUC0-inf will be determined for each age cohort from bezlotoxumab serum concentration data.
    2. Safety: Proportion of participants with any AE and proportion of participants with a discontinuation due to an AE through 12 weeks following infusion.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Any endpoint assessment would need data analysis 12 weeks following a single infusion of bezlotoxumab or placebo
    1. PK/PD endpoint will be assessed at following time points:a) End of Panel A Age Cohort 1 (12 subjects completed 12 wk F/UP) b) end of Panel A Age Cohort 2 (12 subjects completed 12 wk F/UP) c) At the conclusion of this trial, PK data from all participants who received the trial medication and who have sufficient data to assess PK from both Panels A and B will be used to compile an overall bezlotoxumab PK profile in the pediatric population
    2.The safety endpoint will be assessed at following time points :a) End of Panel A Age Cohort 1 (12 subjects completed 12 wk F/UP) b)end of Panel A Age Cohort 2 (12 subjects completed 12 wk F/UP) c) end of study for aggregate data
    E.5.2Secondary end point(s)
    Efficacy:
    1. Proportion of participants who have a CDI recurrence within 12 weeks of study medication infusion
    2. Proportion of participants with sustained clinical response over a period of 12 weeks
    3.Proportion of participants who have a CDI recurrence and proportion of participants who achieve sustained clinical response within 12 weeks of study medication infusion in the subset of participants at high risk for CDI recurrence
    Safety:
    4. Proportion of participants experiencing 1 or more infusion-related reactions within 24 hours following the start of the infusion
    Immunogenicity:
    5. Proportion of participants with treatment-emergent positive antibodies to bezlotoxumab in serum through 12 weeks following a single dose of bezlotoxumab
    E.5.2.1Timepoint(s) of evaluation of this end point
    Any endpoint assessment would need data analysis 12 weeks following administration of a single infusion of bezlotoxumab or placebo.
    All secondary endpoints will be assessed at following time points a) End of Panel A Age Cohort 1 (12 subjects completed 12 wk F/UP); B)end of Panel A Age Cohort 2 (12 subjects completed 12 wk F/UP) and c) end of study for aggregate data
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Stratified by age cohort and with sequential enrollment
    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 Information not present in EudraCT
    E.8.4 The trial involves multiple sites in the Member State concerned Information not present in EudraCT
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA38
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Brazil
    Colombia
    Malaysia
    Mexico
    South Africa
    United States
    Germany
    Hungary
    Norway
    Poland
    Portugal
    Romania
    Spain
    Sweden
    United Kingdom
    Czechia
    Argentina
    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 years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 192
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 6
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 93
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 93
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 101
    F.4.2.2In the whole clinical trial 192
    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 Decision2017-10-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-12-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-05-12
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