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    Clinical Trial Results:
    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)

    Summary
    EudraCT number
    		 2017-000070-11
    Trial protocol
    		 CZ   ES   PT   SE   DE   NO   HU   PL   Outside EU/EEA   GB  
    Global end of trial date
    12 May 2022

    Results information
    Results version number
    		 v1
    This version publication date
    22 Oct 2022
    First version publication date
    22 Oct 2022
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    6072-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03182907
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Protocol Number: MK-6072-001
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001645-PIP01-14
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 May 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    12 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study are to evaluate the pharmacokinetics (PK), safety, and tolerability of bezlotoxumab (MK-6072) in children aged 1 to <18 years of age with a confirmed diagnosis of Clostridium difficile (C. Difficile) infection (CDI) who are receiving antibacterial drug treatment.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 Antibacterial drug treatment (ABD) will be administered for 10-21 days including the duration of ABD prior to the screening visit, during the screening period, and after the infusion of study treatment, per institutional guidelines, at the investigator's discretion. ABD is defined as the receipt of oral metronidazole, oral vancomycin, intravenous (IV) metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Mar 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 19
    Country: Number of subjects enrolled
    Colombia: 4
    Country: Number of subjects enrolled
    Czechia: 24
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Malaysia: 3
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    South Africa: 3
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 32
    Worldwide total number of subjects
    148
    EEA total number of subjects
    74
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    6
    Children (2-11 years)
    80
    Adolescents (12-17 years)
    62
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 148 participants were randomized in the study of which 143 participants received study intervention and were used for safety analysis.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bezlotoxumab
    Arm description
    		 Participants received 10 mg of bezlotoxumab per kg body weight via a single 60-minute (±10 minutes) intravenous (IV) infusion on Day 1. Additionally, participants received background ABD for 10-21 days per institutional guidelines, at the investigator's discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bezlotoxumab
    Investigational medicinal product code
    Other name
    MK-6072
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg of bezlotoxumab per kg body weight via a 60-minute (±10 minutes) IV infusion on Day 1

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo for bezlotoxumab consisting of either 0.9% sodium chloride or 5% dextrose via a single 60-minute (±10 minutes) IV infusion on Day 1. Additionally, participants received background ABD for 10-21 days per institutional guidelines, at the investigator's discretion.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.9% sodium chloride or 5% dextrose via a 60-minute (±10 minutes) IV infusion on Day 1

    Number of subjects in period 1
    		Bezlotoxumab Placebo
    Started
    111
    37
    Treated
    107
    36
    Completed
    103
    35
    Not completed
    8
    2
         Death
    3
    -
         Withdrawal by Parent/Guardian
    -
    2
         Lost to follow-up
    1
    -
         Protocol deviation
    4
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bezlotoxumab
    Reporting group description
    		 Participants received 10 mg of bezlotoxumab per kg body weight via a single 60-minute (±10 minutes) intravenous (IV) infusion on Day 1. Additionally, participants received background ABD for 10-21 days per institutional guidelines, at the investigator's discretion.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo for bezlotoxumab consisting of either 0.9% sodium chloride or 5% dextrose via a single 60-minute (±10 minutes) IV infusion on Day 1. Additionally, participants received background ABD for 10-21 days per institutional guidelines, at the investigator's discretion.

    Reporting group values
    		 Bezlotoxumab Placebo Total
    Number of subjects
    		 111 37 148
    Age Categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.2 ( 5.4 ) 9.3 ( 5.3 ) -
    Gender Categorical
    Units: Participants
        Female
    		 51 18 69
        Male
    		 60 19 79
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 2 0 2
        Asian
    		 3 2 5
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 6 1 7
        White
    		 87 32 119
        More than one race
    		 9 1 10
        Unknown or Not Reported
    		 4 1 5
    Ethnicity
    Units: Subjects
        Hispanic Or Latino
    		 29 9 38
        Not Hispanic Or Latino
    		 72 27 99
        Not Reported
    		 10 1 11

    End points

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    End points reporting groups
    Reporting group title
    Bezlotoxumab
    Reporting group description
    		 Participants received 10 mg of bezlotoxumab per kg body weight via a single 60-minute (±10 minutes) intravenous (IV) infusion on Day 1. Additionally, participants received background ABD for 10-21 days per institutional guidelines, at the investigator's discretion.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo for bezlotoxumab consisting of either 0.9% sodium chloride or 5% dextrose via a single 60-minute (±10 minutes) IV infusion on Day 1. Additionally, participants received background ABD for 10-21 days per institutional guidelines, at the investigator's discretion.

    Subject analysis set title
    Bezlotoxumab: Cohort 1 (12 to <18 years age)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants aged 12 to <18 years of age received 10 mg of bezlotoxumab per kg body weight via a single 60-minute (±10 minutes) IV infusion on Day 1. Additionally, participants received background ABD for 10-21 days per institutional guidelines, at the investigator's discretion.

    Subject analysis set title
    Bezlotoxumab: Cohort 2 (1 to <12 years of age)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants aged 1 to <12 years of age received 10 mg of bezlotoxumab per kg body weight via a single 60-minute (±10 minutes) IV infusion on Day 1. Additionally, participants received background ABD for 10-21 days per institutional guidelines, at the investigator's discretion.

    Primary: Area Under the Concentration-Time Curve of Bezlotoxumab From Time 0 to Infinity (AUC 0-inf)

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    End point title
    		 Area Under the Concentration-Time Curve of Bezlotoxumab From Time 0 to Infinity (AUC 0-inf) [1]
    End point description
    Blood samples were collected at specified intervals for the determination of AUC0-inf. AUC0-inf was defined as the area under the concentration-time curve of bezlotoxumab from time zero to infinity. The analysis population included all participants who received bezlotoxumab, had at least 4 postdose AUC0-inf samples and complied with the protocol. Per protocol, AUC0-inf of bezlotoxumab was determined for each age cohort.
    End point type
    Primary
    End point timeframe
    Day 1 (2 hours postdose), Days 10, 29, 57, and 85
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no between arm statistical analysis planned for this endpoint.
    End point values
    		 Bezlotoxumab: Cohort 1 (12 to <18 years age) Bezlotoxumab: Cohort 2 (1 to <12 years of age)
    Number of subjects analysed
    36
    54
    Units: hr*ug/mL
        geometric mean (confidence interval 95%)
    56100 (49400 to 63700)
    43200 (38900 to 47900)
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Experienced an Adverse Event (AE)

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    End point title
    		 Percentage of Participants Who Experienced an Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product and does not imply any judgment about causality. The analysis population included all participants who received study intervention. Per protocol, percentage of participants with AEs in the bezlotoxumab and placebo groups were presented.
    End point type
    Primary
    End point timeframe
    Up to approximately 12 weeks
    End point values
    		 Bezlotoxumab Placebo
    Number of subjects analysed
    107
    36
    Units: Percentage of participants
        number (not applicable)
    88.8
    94.4
    Statistical analysis title
    		 Estimated difference in percentage
    Comparison groups
    Bezlotoxumab v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -5.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.5
         upper limit
    		 7.7
    Notes
    [2] - Miettinen & Nurminen method was used to generate the estimated difference in percentage and associated 95% confidence intervals (CIs) in bezlotoxumab versus placebo arms.

    Primary: Percentage of Participants Who Discontinued Study Due to an AE

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    End point title
    		 Percentage of Participants Who Discontinued Study Due to an AE
    End point description
    An AE was defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product and does not imply any judgment about causality. The analysis population included all participants who received study intervention. Per protocol, percentage of participants who discontinued study due to AEs in the bezlotoxumab and placebo groups were presented.
    End point type
    Primary
    End point timeframe
    Up to approximately 12 weeks
    End point values
    		 Bezlotoxumab Placebo
    Number of subjects analysed
    107
    36
    Units: Percentage of participants
        number (not applicable)
    0
    0
    Statistical analysis title
    		 Estimated difference in percentage
    Comparison groups
    Bezlotoxumab v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.7
         upper limit
    		 3.5
    Notes
    [3] - Miettinen & Nurminen method was used to generate the estimated difference in percentage and associated 95% CIs in bezlotoxumab versus placebo arms.

    Secondary: Percentage of Participants Who Had a Clostridium Difficile Infection (CDI) Recurrence

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    End point title
    		 Percentage of Participants Who Had a Clostridium Difficile Infection (CDI) Recurrence
    End point description
    CDI recurrence was defined as diarrhea recurrence (new episode of diarrhea after initial clinical response [ICR] as defined by a change in normal bowel habits for ≥2 days with either watery diarrhea or at least 6 unformed bowel movements [UBMs] within 48-hours) associated with a positive stool test for C. difficile toxin, and for which the participant, in the investigator's opinion, requires and receives ABD treatment for CDI. The analysis population included all participants who received any amount of study intervention, had positive local stool for C. difficile toxin, were taking protocol-defined ABD treatment for CDI on the day of infusion, and achieved an ICR of baseline CDI. Per protocol, percentage of participants who had a CDI recurrence in the bezlotoxumab and placebo groups were reported.
    End point type
    Secondary
    End point timeframe
    Up to approximately 12 Weeks
    End point values
    		 Bezlotoxumab Placebo
    Number of subjects analysed
    98
    34
    Units: Percentage of participants
        number (not applicable)
    11.2
    14.7
    Statistical analysis title
    		 Treatment difference
    Comparison groups
    Bezlotoxumab v Placebo
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.5701
    Method
    		 Stratified Miettinen and Nurminen method
    Parameter type
    		 Adjusted difference
    Point estimate
    -3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20
         upper limit
    		 8
    Notes
    [4] - Miettinen and Nurminen method stratified by age cohort (12 to <18 years of age, 1 to <12 years of age) with a Cochran-Mantel-Haenszel weight was used to generate the treatment difference, associated 95% CIs and a 2-sided p-value.

    Secondary: Percentage of Participants Who Had a Sustained Clinical Response (SCR)

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    End point title
    		 Percentage of Participants Who Had a Sustained Clinical Response (SCR)
    End point description
    SCR was defined as the ICR of baseline CDI episode (improvement in number and character of bowel movements and doesn’t require further CDI therapy within 2 days after completion of up to 21 days of ABD treatment for CDI) and no CDI recurrence (diarrhea recurrence associated with a positive stool test for C. difficile toxin, and for which the participant, in investigator's opinion, requires and receives ABD for CDI). The analysis population included all participants who received any amount of study intervention, had positive local stool for C. difficile toxin, and were taking protocol-defined ABD treatment for CDI on the day of infusion. Per protocol, percentage of participants who had a SCR in bezlotoxumab and placebo groups were presented.
    End point type
    Secondary
    End point timeframe
    Up to approximately 12 Weeks
    End point values
    		 Bezlotoxumab Placebo
    Number of subjects analysed
    104
    35
    Units: Percentage of participants
        number (not applicable)
    83.7
    82.9
    Statistical analysis title
    		 Treatment difference
    Comparison groups
    Bezlotoxumab v Placebo
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.9165
    Method
    		 Stratified Miettinen and Nurminen method
    Parameter type
    		 Adjusted difference
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.8
         upper limit
    		 17.6
    Notes
    [5] - Miettinen and Nurminen method stratified by age cohort (12 to <18 years of age, 1 to <12 years of age) with a Cochran-Mantel-Haenszel weight was used to generate the treatment difference, associated 95% CIs and a 2-sided p-value.

    Secondary: Percentage of High-Risk Participants Who Experienced a CDI Recurrence

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    End point title
    		 Percentage of High-Risk Participants Who Experienced a CDI Recurrence
    End point description
    CDI recurrence was defined as diarrhea recurrence (new diarrhea episode after ICR defined by change in normal bowel habits for ≥2 days with watery diarrhea or at least 6 UBMs within 48-hours) with positive stool test for C. difficile toxin for which participant, in investigator's opinion, requires and receives ABD for CDI. High-risk was meeting ≥1 criteria at/before randomization: a) was immunocompromised b) had ≥1 CDI episode prior to baseline episode c) had severe CDI baseline episode d) had C. difficile ribotype027 in stool at baseline CDI episode e) received ≥1 systemic ABD known to increase CDI risk. The analysis population included all participants who received study intervention, had positive local stool for C. difficile toxin, were taking ABD for CDI on infusion day, achieved ICR of baseline CDI, and were at high-risk of CDI recurrence. Per protocol, percentage of high-risk participants who experienced a CDI recurrence in the bezlotoxumab and placebo groups were presented.
    End point type
    Secondary
    End point timeframe
    Up to approximately 12 Weeks
    End point values
    		 Bezlotoxumab Placebo
    Number of subjects analysed
    91
    33
    Units: Percentage of participants
        number (not applicable)
    12.1
    15.2
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Bezlotoxumab v Placebo
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.6542
    Method
    		 Unstratified Miettinen & Nurminen method
    Parameter type
    		 Adjusted Difference
    Point estimate
    -3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.9
         upper limit
    		 9
    Notes
    [6] - Unstratified Miettinen and Nurminen method was used to generate the treatment difference, associated 95% CIs and a 2-sided p-value.

    Secondary: Percentage of High-Risk Participants Who Experienced a SCR

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    End point title
    		 Percentage of High-Risk Participants Who Experienced a SCR
    End point description
    SCR was ICR of baseline CDI episode (improvement in number and character of bowel movements and doesn’t require further CDI therapy within 2 days after completion of upto 21 days of ABD for CDI) and no CDI recurrence (diarrhea recurrence with positive stool test for C. difficile toxin, for which participant, in investigator's opinion, requires and receives ABD for CDI). High-risk was meeting ≥1 criteria: a) was immunocompromised b) had ≥1 episodes of CDI prior to baseline episode c) had severe CDI baseline episode d) had C. difficile ribotype027 in stool at baseline CDI episode e) received ≥1 systemic ABD known to increase CDI risk. The analysis population included all participants who received study intervention, had positive local stool for C. difficile toxin, were taking protocol-defined ABD for CDI on the day of infusion, and were at high risk of CDI recurrence. Per protocol, percentage of high-risk participants who had SCR in bezlotoxumab and placebo groups were presented.
    End point type
    Secondary
    End point timeframe
    Up to approximately 12 Weeks
    End point values
    		 Bezlotoxumab Placebo
    Number of subjects analysed
    97
    34
    Units: Percentage of participants
        number (not applicable)
    82.5
    82.4
    Statistical analysis title
    		 Treatment difference
    Comparison groups
    Bezlotoxumab v Placebo
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.9873
    Method
    		 Unstratified Miettinen & Nurminen method
    Parameter type
    		 Adjusted difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13
         upper limit
    		 17.4
    Notes
    [7] - Unstratified Miettinen and Nurminen method was used to generate treatment difference, associated 95% CIs and a 2-sided p-value.

    Secondary: Percentage of Participants Who Experienced One or More Infusion Related Reaction

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    End point title
    		 Percentage of Participants Who Experienced One or More Infusion Related Reaction
    End point description
    Infusion related reaction included events meeting any of the 3 criteria: 1) acute onset of an illness involving skin, mucosal tissue, or both and at least 1 of the following: respiratory compromise, reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 2) two or more of the following after onset of study infusion: involving skin-mucosal tissue, respiratory compromise, reduced BP or associated symptoms, or persistent gastrointestinal symptoms 3) reduced BP after onset of infusion or >30% decrease in systolic BP from baseline. The analysis population included all participants who received study intervention. Per protocol, percentage of participants experiencing 1 or more infusion-related reactions within 24 hours following the start of study medication infusion were reported.
    End point type
    Secondary
    End point timeframe
    Up to approximately 24 hours after infusion on Day 1
    End point values
    		 Bezlotoxumab Placebo
    Number of subjects analysed
    107
    36
    Units: Percentage of participants
        number (not applicable)
    0.09
    2.78
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Had Positive Antibodies to Bezlotoxumab

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    End point title
    		 Percentage of Participants Who Had Positive Antibodies to Bezlotoxumab
    End point description
    Blood samples were collected to determine antibodies to bezlotoxumab. The analysis population included all participants who received any amount of bezlotoxumab, had a positive local stool for C. difficile toxin, were taking protocol-defined ABD drug treatment for CDI on the day of infusion, and achieved an ICR of baseline CDI. Per protocol, percentage of participants with treatment-emergent positive antibodies to bezlotoxumab following single infusion of bezlotoxumab were reported for each age cohort.
    End point type
    Secondary
    End point timeframe
    Up to approximately 12 Weeks
    End point values
    		 Bezlotoxumab: Cohort 1 (12 to <18 years age) Bezlotoxumab: Cohort 2 (1 to <12 years of age)
    Number of subjects analysed
    44
    62
    Units: Percentage of participants
        number (not applicable)
    2.4
    1.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 14 months
    Adverse event reporting additional description
    All cause mortality was reported on all randomized participants and non-serious and serious AEs were reported on all participants who received study intervention.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo for bezlotoxumab consisting of either 0.9% sodium chloride or 5% dextrose via a single 60-minute (±10 minutes) IV infusion on Day 1. Additionally, participants received background ABD for 10-21 days per institutional guidelines, at the investigator's discretion.

    Reporting group title
    Bezlotoxumab
    Reporting group description
    		 Participants received 10 mg of bezlotoxumab per kg body weight via a single 60-minute (±10 minutes) intravenous (IV) infusion on Day 1. Additionally, participants received background ABD for 10-21 days per institutional guidelines, at the investigator's discretion.

    Serious adverse events
    		 Placebo Bezlotoxumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 36 (80.56%)
    57 / 107 (53.27%)
         number of deaths (all causes)
    1
    6
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Leukaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasm progression
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroblastoma
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Venoocclusive disease
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 36 (8.33%)
    4 / 107 (3.74%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft versus host disease
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract oedema
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurotoxicity
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nystagmus
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    11 / 36 (30.56%)
    22 / 107 (20.56%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 107 (2.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 107 (2.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal inflammation
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary-bronchial fistula
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myopathy
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acinetobacter sepsis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    COVID-19
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter bacteraemia
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal sepsis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis sapovirus
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nosocomial infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 107 (2.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 107 (2.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Serratia bacteraemia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 36 (2.78%)
    4 / 107 (3.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 36 (5.56%)
    3 / 107 (2.80%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval cellulitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Bezlotoxumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 36 (77.78%)
    65 / 107 (60.75%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 36 (0.00%)
    9 / 107 (8.41%)
         occurrences all number
    0
    12
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 36 (0.00%)
    8 / 107 (7.48%)
         occurrences all number
    0
    8
    C-reactive protein increased
         subjects affected / exposed
    2 / 36 (5.56%)
    4 / 107 (3.74%)
         occurrences all number
    3
    4
    Injury, poisoning and procedural complications
    Transfusion reaction
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 107 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 36 (19.44%)
    15 / 107 (14.02%)
         occurrences all number
    8
    22
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 36 (16.67%)
    8 / 107 (7.48%)
         occurrences all number
    10
    8
    Leukopenia
         subjects affected / exposed
    2 / 36 (5.56%)
    4 / 107 (3.74%)
         occurrences all number
    2
    4
    Febrile neutropenia
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 107 (0.93%)
         occurrences all number
    2
    2
    Thrombocytopenia
         subjects affected / exposed
    3 / 36 (8.33%)
    7 / 107 (6.54%)
         occurrences all number
    3
    8
    Neutropenia
         subjects affected / exposed
    2 / 36 (5.56%)
    7 / 107 (6.54%)
         occurrences all number
    2
    7
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    8 / 36 (22.22%)
    15 / 107 (14.02%)
         occurrences all number
    12
    22
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 36 (16.67%)
    13 / 107 (12.15%)
         occurrences all number
    10
    28
    Constipation
         subjects affected / exposed
    2 / 36 (5.56%)
    7 / 107 (6.54%)
         occurrences all number
    2
    11
    Diarrhoea
         subjects affected / exposed
    5 / 36 (13.89%)
    8 / 107 (7.48%)
         occurrences all number
    14
    9
    Nausea
         subjects affected / exposed
    4 / 36 (11.11%)
    7 / 107 (6.54%)
         occurrences all number
    5
    10
    Stomatitis
         subjects affected / exposed
    2 / 36 (5.56%)
    8 / 107 (7.48%)
         occurrences all number
    2
    10
    Vomiting
         subjects affected / exposed
    8 / 36 (22.22%)
    14 / 107 (13.08%)
         occurrences all number
    12
    16
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 36 (5.56%)
    3 / 107 (2.80%)
         occurrences all number
    2
    4
    Dyspnoea
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 107 (0.93%)
         occurrences all number
    2
    1
    Nasal congestion
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 107 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 107 (0.00%)
         occurrences all number
    2
    0
    Erythema
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 107 (0.00%)
         occurrences all number
    2
    0
    Urticaria
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 107 (0.93%)
         occurrences all number
    2
    1
    Vancomycin infusion reaction
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 107 (0.93%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 36 (8.33%)
    2 / 107 (1.87%)
         occurrences all number
    3
    2
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 107 (0.00%)
         occurrences all number
    2
    0
    Oral herpes
         subjects affected / exposed
    2 / 36 (5.56%)
    5 / 107 (4.67%)
         occurrences all number
    4
    5
    Rhinitis
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 107 (1.87%)
         occurrences all number
    3
    2
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 107 (0.93%)
         occurrences all number
    2
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 107 (0.93%)
         occurrences all number
    2
    1
    Hypokalaemia
         subjects affected / exposed
    6 / 36 (16.67%)
    8 / 107 (7.48%)
         occurrences all number
    6
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Mar 2019
    The major changes of amendment 1 were shortening the enrollment timeline by removing the pre-specified enrollment pause for pharmacokinetic evaluation and determining that dose modifications were not needed.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    22 Feb 2019
    Amendment 1 submission to eliminate pre-specified enrollment pauses.
    21 Mar 2019
    09 Mar 2022
    Proposal submission to European Union Pediatric Committee (EU PDCO) and the United States Food and Drug Administration (US FDA) to request concurrence with plan to conclude enrollment. The enrollment was not restarted.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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