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    Clinical Trial Results:
    A Phase 2, Randomized, Active Comparator-Controlled, Multicenter, Double-Blind Clinical Trial to Study the Safety and Efficacy of Ceftolozane/Tazobactam (MK-7625A) Plus Metronidazole Versus Meropenem in Pediatric Subjects with Complicated Intra-Abdominal Infection

    Summary
    EudraCT number
    		 2016-004820-41
    Trial protocol
    		 LT   ES   HU   Outside EU/EEA  
    Global end of trial date
    20 Jan 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    26 Jan 2022
    First version publication date
    23 Jul 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    7625A-035
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03217136
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001142-PIP01-11
    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
    16 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study aims to evaluate the safety and tolerability of MK-7625A (ceftolozane/tazobactam) plus metronidazole, compared with that of meropenem in pediatric participants with complicated intra-abdominal infection (cIAI).
    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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Apr 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: 1
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Lithuania: 8
    Country: Number of subjects enrolled
    Malaysia: 3
    Country: Number of subjects enrolled
    Mexico: 16
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    South Africa: 6
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    Ukraine: 12
    Country: Number of subjects enrolled
    United States: 18
    Worldwide total number of subjects
    94
    EEA total number of subjects
    29
    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)
    2
    Children (2-11 years)
    69
    Adolescents (12-17 years)
    23
    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
    		 This study enrolled 94 paediatric participants from 27 sites in 11 countries.

    Pre-assignment
    Screening details
    		 Of participants screened, 94 participants were randomized, and 91 received study drug.

    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, Monitor, Carer, Assessor
    Blinding implementation details
    Blinding applied only to intravenous (IV) drugs. Participants were not blinded to drugs administered as part of oral step-down therapy.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 C/T+MTZ
    Arm description
    		 Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftolozane + tazobactam
    Investigational medicinal product code
    Other name
    MK-7625A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For participants aged birth to <12 years of age: 20 mg/kg ceftolozane + 10 mg/kg tazobactam, intravenous every 8 hours. Maximum dose was 1 g of ceftolozane and 0.5 g of tazobactam. For participants 12 to <18 years of age: 1 g ceftolozane + 0.5 g tazobactam, intravenous every 8 hours.

    Investigational medicinal product name
    Standard of Care Oral Therapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    After receiving at least 9 doses of double-blind, IV study treatment, participants could have switched to open-label, standard of care, oral step-down antibiotic therapy at the investigator’s discretion: β-lactam/β-lactamase inhibitor combination, Second or third generation cephalosporin in combination with metronidazole, or Quinolone standard of care. If ciprofloxacin or levofloxacin were chosen, they were to be used in combination with metronidazole. Total antibiotic duration (IV only or IV + oral) was a minimum of 5 days to a maximum of 14 days. Optional oral step-down therapy is considered study treatment in this study.

    Investigational medicinal product name
    Metronidazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous metronidazole. For participants >28 days of age: 10 mg/kg, every 8 hours. For participants ≤28 days of age and ≤2 kg: 15 mg/kg loading dose then 7.5 mg/kg every 12 hours. For participants ≤28 days of age and >2 kg 15 mg/kg loading dose then 10 mg/kg every 12 hours. Maximum of 1.5 g per dose.

    Arm title
    		 MERO
    Arm description
    		 Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for metronidazole administered IV every 8 hours for 5 to 14 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Meropenem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous meropenem, 20 mg/kg every 8 hours. Maximum of 1 g per dose.

    Investigational medicinal product name
    Placebo for metronidazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous placebo for metronidazole every 8 hours.

    Investigational medicinal product name
    Standard of Care Oral Therapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    After receiving at least 9 doses of double-blind, IV study treatment, participants could have switched to open-label, standard of care, oral step-down antibiotic therapy at the investigator’s discretion: β-lactam/β-lactamase inhibitor combination, Second or third generation cephalosporin in combination with metronidazole, or Quinolone standard of care. If ciprofloxacin or levofloxacin were chosen, they were to be used in combination with metronidazole. Total antibiotic duration (IV only or IV + oral) was a minimum of 5 days to a maximum of 14 days. Optional oral step-down therapy is considered study treatment in this study.

    Number of subjects in period 1
    		C/T+MTZ MERO
    Started
    71
    23
    Treated
    70
    21
    Completed
    67
    20
    Not completed
    4
    3
         Dispensing Error
    1
    -
         Withdrawal by Parent/Guardian
    1
    -
         Site Randomized Participant in Error
    -
    1
         Did Not Meet Criteria after Randomization
    -
    1
         Lost to follow-up
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    C/T+MTZ
    Reporting group description
    		 Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days.

    Reporting group title
    MERO
    Reporting group description
    		 Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for metronidazole administered IV every 8 hours for 5 to 14 days.

    Reporting group values
    		 C/T+MTZ MERO Total
    Number of subjects
    		 71 23 94
    Age Categorical
    Units: Participants
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 2 0 2
        Children (2-11 years)
    		 52 17 69
        Adolescents (12-17 years)
    		 17 6 23
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender Categorical
    Units: Participants
        Female
    		 23 15 38
        Male
    		 48 8 56
    Race
    Units: Subjects
        Asian
    		 3 2 5
        Black Or African American
    		 6 1 7
        More than one race
    		 1 0 1
        White
    		 61 20 81
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 18 7 25
        Not Hispanic or Latino
    		 50 16 66
        Unknown or Not Reported
    		 3 0 3

    End points

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    End points reporting groups
    Reporting group title
    C/T+MTZ
    Reporting group description
    		 Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days.

    Reporting group title
    MERO
    Reporting group description
    		 Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for metronidazole administered IV every 8 hours for 5 to 14 days.

    Primary: Number of Participants Experiencing ≥1 Adverse Events (AEs)

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    End point title
    		 Number of Participants Experiencing ≥1 Adverse Events (AEs)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE is presented. The analysis population consisted of all randomized participants who received any amount of study treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 75 days
    End point values
    		 C/T+MTZ MERO
    Number of subjects analysed
    70
    21
    Units: Participants
    56
    13
    Statistical analysis title
    		 Difference in Percentage (C/T+MTZ minus MERO)
    Statistical analysis description
    The Miettinen & Nurminen method was used.
    Comparison groups
    MERO v C/T+MTZ
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    18.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 41.1

    Primary: Number of Participants Who Discontinued Study Therapy Due to AE(s)

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    End point title
    		 Number of Participants Who Discontinued Study Therapy Due to AE(s)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE is presented. The analysis population consisted of all randomized participants who received any amount of study treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 18 days
    End point values
    		 C/T+MTZ MERO
    Number of subjects analysed
    70
    21
    Units: Participants
    2
    0
    Statistical analysis title
    		 Difference in Percentage (C/T+MTZ minus MERO)
    Statistical analysis description
    The Miettinen & Nurminen method was used.
    Comparison groups
    C/T+MTZ v MERO
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.9
         upper limit
    		 9.9

    Secondary: Percentage of Participants with a Clinical Response of "Cure" at the End of Treatment (EOT) Visit

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    End point title
    		 Percentage of Participants with a Clinical Response of "Cure" at the End of Treatment (EOT) Visit
    End point description
    The percentage of participants who had a clinical outcome of "cure" at the time of the EOT visit is presented. The "cure" clinical outcome was defined as complete resolution or marked improvement in signs and symptoms of the complicated intra-abdominal infection (cIAI) or return to preinfection signs and symptoms such that no further antibiotic therapy (intravenous or oral) or surgical or drainage procedure is required for treatment of the cIAI. Participants who were missing clinical response data were considered treatment failures. The analysis population consisted of all randomized participants who received any amount of study treatment. Participants were included in the IV study treatment group to which they were randomized, irrespective of what treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 days
    End point values
    		 C/T+MTZ MERO
    Number of subjects analysed
    70
    21
    Units: Percentage of Participants
        number (confidence interval 95%)
    80.0 (69.18 to 87.70)
    95.2 (77.33 to 99.15)
    Statistical analysis title
    		 Difference in Percentage (C/T+MTZ minus MERO)
    Statistical analysis description
    The Miettinen & Nurminen method stratified by age group with Cochran-Mantel-Haenszel (CMH) weights was used. If there was a zero count in any class of the stratum, the groups with the lower count were pooled with its near age group stratum in the model.
    Comparison groups
    C/T+MTZ v MERO
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -14.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.67
         upper limit
    		 4.93

    Secondary: Percentage of Participants with a Clinical Response of "Cure" at the Test of Cure (TOC) Visit

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    End point title
    		 Percentage of Participants with a Clinical Response of "Cure" at the Test of Cure (TOC) Visit
    End point description
    The percentage of participants who had a clinical outcome of "cure" at the time of the TOC visit is presented. The "cure" clinical outcome was defined as complete resolution or marked improvement in signs and symptoms of the complicated intra-abdominal infection (cIAI) or return to preinfection signs and symptoms such that no further antibiotic therapy (intravenous or oral) or surgical or drainage procedure is required for treatment of the cIAI. Participants who were missing clinical response data were considered treatment failures. The analysis population consisted of all randomized participants who received any amount of study treatment. Participants were included in the IV study treatment group to which they were randomized, irrespective of what treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Up to approximately 39 days
    End point values
    		 C/T+MTZ MERO
    Number of subjects analysed
    70
    21
    Units: Percentage of Participants
        number (confidence interval 95%)
    80.0 (69.18 to 87.70)
    100.0 (84.54 to 100.0)
    Statistical analysis title
    		 Difference in Percentage (C/T+MTZ minus MERO)
    Statistical analysis description
    The Miettinen & Nurminen method stratified by age group with Cochran-Mantel-Haenszel (CMH) weights was used. If there was a zero count in any class of the stratum, the groups with the lower count were pooled with its near age group stratum in the model.
    Comparison groups
    C/T+MTZ v MERO
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -19.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.18
         upper limit
    		 -2.89

    Secondary: Per-Participant Microbiological Eradication at the End of Treatment (EOT) Visit

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    End point title
    		 Per-Participant Microbiological Eradication at the End of Treatment (EOT) Visit
    End point description
    The percentage of participants who achieved either eradication or presumed eradication of each baseline infecting pathogen by the time of the EOT visit is presented. Eradication was defined as absence of the baseline pathogen(s) in a postbaseline specimen appropriately obtained from the original site of infection. Presumed eradication was defined as absence of material to culture in a participant who is assessed as having partial improvement, or clinical cure. In the event of multiple baseline pathogens, the least favorable microbiological response from all possible baseline pathogens was used. The analysis population consisted of all randomized participants who received any amount of study treatment and had at least 1 pathogen identified from the baseline intra-abdominal culture, regardless of susceptibility to study treatment. Participants were included in the IV study treatment group to which they were randomized, irrespective of what treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 days
    End point values
    		 C/T+MTZ MERO
    Number of subjects analysed
    63
    19
    Units: Percentage of Participants
        number (confidence interval 95%)
    84.1 (73.19 to 91.14)
    94.7 (75.36 to 99.06)
    Statistical analysis title
    		 Difference in Percentage (C/T+MTZ minus MERO)
    Statistical analysis description
    The Miettinen & Nurminen method stratified by age group with Cochran-Mantel-Haenszel (CMH) weights was used. If there was a zero count in any class of the stratum, the groups with the lower count were pooled with its near age group stratum in the model.
    Comparison groups
    C/T+MTZ v MERO
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -11.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.66
         upper limit
    		 9.61

    Secondary: Per-Participant Microbiological Eradication at the Test of Cure (TOC) Visit

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    End point title
    		 Per-Participant Microbiological Eradication at the Test of Cure (TOC) Visit
    End point description
    The percentage of participants who achieved either eradication or presumed eradication of each baseline infecting pathogen by the time of the TOC visit is presented. Eradication was defined as absence of the baseline pathogen(s) in a postbaseline specimen appropriately obtained from the original site of infection. Presumed eradication was defined as absence of material to culture in a participant who is assessed as having partial improvement, or clinical cure. In the event of multiple baseline pathogens, the least favorable microbiological response from all possible baseline pathogens was used. The analysis population consisted of all randomized participants who received any amount of study treatment and had at least 1 pathogen identified from the baseline intra-abdominal culture, regardless of susceptibility to study treatment. Participants were included in the IV study treatment group to which they were randomized, irrespective of what treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Up to approximately 39 days
    End point values
    		 C/T+MTZ MERO
    Number of subjects analysed
    63
    19
    Units: Percentage of Participants
        number (confidence interval 95%)
    84.1 (73.19 to 91.14)
    100 (83.18 to 100.00)
    Statistical analysis title
    		 Difference in Percentage (C/T+MTZ minus MERO)
    Statistical analysis description
    The Miettinen & Nurminen method stratified by age group with Cochran-Mantel-Haenszel (CMH) weights was used. If there was a zero count in any class of the stratum, the groups with the lower count were pooled with its near age group stratum in the model.
    Comparison groups
    C/T+MTZ v MERO
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -16.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.59
         upper limit
    		 1.39

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 75 days
    Adverse event reporting additional description
    Deaths are counted in the population of all randomized participants. Serious adverse events and non-serious adverse events are reported for all randomized participants who received any amount of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    C/T + MTZ
    Reporting group description
    		 Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days.

    Reporting group title
    MERO
    Reporting group description
    		 Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for metronidazole administered IV every 8 hours for 5 to 14 days.

    Serious adverse events
    		 C/T + MTZ MERO
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 70 (11.43%)
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    White blood cell count increased
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal fluid collection
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 C/T + MTZ MERO
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 70 (65.71%)
    10 / 21 (47.62%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 70 (5.71%)
    1 / 21 (4.76%)
         occurrences all number
    4
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 70 (7.14%)
    1 / 21 (4.76%)
         occurrences all number
    5
    1
    Platelet count increased
         subjects affected / exposed
    5 / 70 (7.14%)
    2 / 21 (9.52%)
         occurrences all number
    5
    2
    Injury, poisoning and procedural complications
    Incision site pain
         subjects affected / exposed
    7 / 70 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    7
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 70 (5.71%)
    0 / 21 (0.00%)
         occurrences all number
    4
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    5 / 70 (7.14%)
    1 / 21 (4.76%)
         occurrences all number
    5
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 70 (5.71%)
    0 / 21 (0.00%)
         occurrences all number
    4
    0
    Thrombocytosis
         subjects affected / exposed
    6 / 70 (8.57%)
    1 / 21 (4.76%)
         occurrences all number
    6
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 70 (12.86%)
    3 / 21 (14.29%)
         occurrences all number
    10
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 70 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    8
    0
    Diarrhoea
         subjects affected / exposed
    13 / 70 (18.57%)
    5 / 21 (23.81%)
         occurrences all number
    14
    5
    Vomiting
         subjects affected / exposed
    7 / 70 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    8
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 70 (4.29%)
    3 / 21 (14.29%)
         occurrences all number
    3
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jun 2019
    Amendment 2: Enrollment targets for participants aged birth to <6 years of age were applied.
    23 Sep 2020
    Amendment 3: Due to enrollment challenges, enrollment targets for participants aged birth to <6 years of age were adjusted.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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