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    Clinical Trial Results:
    A Phase 3, Multicenter, Investigator-blind, Randomized, Parallel Group Study to Investigate the Safety and Efficacy of Fidaxomicin Oral Suspension or Tablets Taken q12h, and Vancomycin Oral Liquid or Capsules Taken q6h, for 10 Days in Pediatric Subjects with Clostridium difficile-associated Diarrhea

    Summary
    EudraCT number
    2013-000508-40
    Trial protocol
    DE   BE   SK   PL   IT   ES   HU   FR  
    Global end of trial date
    07 Mar 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Sep 2018
    First version publication date
    15 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2819-CL-0202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02218372
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Acronym: SUNSHINE
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe B.V.
    Sponsor organisation address
    Sylviusweg 62, Leiden, Netherlands, 2333 BE
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Europe B.V., astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Europe B.V., astellas.resultsdisclosure@astellas.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000636-PIP01-09
    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
    07 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to investigate the clinical response to fidaxomicin granules for oral suspension or tablets and vancomycin oral liquid or capsules of pediatric participants with Clostridium Difficile-Associated Diarrhea (CDAD) from birth to < 18 years of age.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Jan 2015
    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
    Belgium: 7
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Hungary: 17
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    United States: 57
    Worldwide total number of subjects
    148
    EEA total number of subjects
    90
    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)
    30
    Children (2-11 years)
    89
    Adolescents (12-17 years)
    29
    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
    Pediatric participants with clostridium difficile-associated diarrhea (CDAD) were enrolled in this multicenter study.

    Pre-assignment
    Screening details
    Eligible participants who met inclusion criteria and none of the exclusion criteria were enrolled, 159 participants were assessed for eligibility of whom 148 were randomized. Participants were randomized to either fidaxomicin or vancomycin in a 2:1 ratio, stratified by age group.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Investigator [1]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Fidaxomicin
    Arm description
    Participants from birth to < 6 years of age received weight based doses of fidaxomicin oral suspension (32 mg/kg/day with a maximum dose of 400 mg/day divided in 2 doses) 2 times daily for 10 days. Participants aged ≥ 6 years to < 18 years of age received a 200 mg fidaxomicin tablet 2 times daily for 10 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Fidaxomicin tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants aged ≥ 6 years to < 18 years of age received a 200 mg fidaxomicin tablet 2 times daily for 10 days.

    Investigational medicinal product name
    Fidaxomicin oral suspension
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants from birth to < 6 years of age received weight based doses of fidaxomicin oral suspension (32 mg/kg/day with a maximum dose of 400 mg/day, divided in 2 doses) 2 times daily for 10 days.

    Arm title
    Vancomycin
    Arm description
    Participants from birth to < 6 years of age received weight based doses of vancomycin oral liquid (40 mg/kg/day with a maximum dose of 500 mg/day divided in 4 doses) 4 times daily for 10 days. Participants aged ≥ 6 years to < 18 years of age received a 125 mg vancomycin capsule 4 times daily for 10 days.
    Arm type
    Active comparator

    Investigational medicinal product name
    Vancomycin oral liquid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Participants from birth to < 6 years of age received weight based doses of vancomycin oral liquid (40 mg/kg/day with a maximum dose of 500 mg/day divided in 4 doses) 4 times daily for 10 days.

    Investigational medicinal product name
    Vancomycin capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants aged ≥ 6 years to < 18 years of age received a 125 mg vancomycin capsule 4 times daily for 10 days.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Double blinding of the study drug for this pediatric study population was not feasible, given dosing constraints, the study was investigator-blinded only.
    Number of subjects in period 1
    Fidaxomicin Vancomycin
    Started
    100
    48
    Treated
    98
    44
    Completed
    95
    42
    Not completed
    5
    6
         Miscellaneous
    2
    1
         Adverse event
    1
    1
         Withdrawal by Parent/Guardian
    -
    1
         Randomized but did not receive treatment
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fidaxomicin
    Reporting group description
    Participants from birth to < 6 years of age received weight based doses of fidaxomicin oral suspension (32 mg/kg/day with a maximum dose of 400 mg/day divided in 2 doses) 2 times daily for 10 days. Participants aged ≥ 6 years to < 18 years of age received a 200 mg fidaxomicin tablet 2 times daily for 10 days.

    Reporting group title
    Vancomycin
    Reporting group description
    Participants from birth to < 6 years of age received weight based doses of vancomycin oral liquid (40 mg/kg/day with a maximum dose of 500 mg/day divided in 4 doses) 4 times daily for 10 days. Participants aged ≥ 6 years to < 18 years of age received a 125 mg vancomycin capsule 4 times daily for 10 days.

    Reporting group values
    Fidaxomicin Vancomycin Total
    Number of subjects
    100 48
    Age categorical
    Units: Subjects
    Age continuous
    The baseline analysis set consisted of the Intent-to-treat (ITT) population. The ITT analysis set consisted of all randomized participants, irrespective of a participant having received a study drug (fidaxomicin or vancomycin) or not.
    Units: months
        arithmetic mean (standard deviation)
    79.7 ± 61.8 77.5 ± 59.2 -
    Gender categorical
    Units: Subjects
        Female
    41 21 62
        Male
    59 27 86
    Race
    Units: Subjects
        WHITE
    83 36 119
        BLACK OR AFRICAN AMERICAN
    6 5 11
        ASIAN
    2 0 2
        OTHER
    4 1 5
        MISSING
    5 6 11
    Ethnicity
    Units: Subjects
        HISPANIC OR LATINO
    12 5 17
        NOT HISPANIC OR LATINO
    82 37 119
        MISSING
    6 6 12

    End points

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    End points reporting groups
    Reporting group title
    Fidaxomicin
    Reporting group description
    Participants from birth to < 6 years of age received weight based doses of fidaxomicin oral suspension (32 mg/kg/day with a maximum dose of 400 mg/day divided in 2 doses) 2 times daily for 10 days. Participants aged ≥ 6 years to < 18 years of age received a 200 mg fidaxomicin tablet 2 times daily for 10 days.

    Reporting group title
    Vancomycin
    Reporting group description
    Participants from birth to < 6 years of age received weight based doses of vancomycin oral liquid (40 mg/kg/day with a maximum dose of 500 mg/day divided in 4 doses) 4 times daily for 10 days. Participants aged ≥ 6 years to < 18 years of age received a 125 mg vancomycin capsule 4 times daily for 10 days.

    Subject analysis set title
    Fidaxomin all formulations
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received either fidaxomicin oral suspension or tablet formulation.

    Subject analysis set title
    Fidaxomicin oral suspension
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received fidaxomicin oral suspension formulation.

    Subject analysis set title
    Fidaxomicin tablets
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received fidaxomicin tablets formulation.

    Subject analysis set title
    Vancomycin oral liquid
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received vancomycin oral liquid formulation.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all randomized participants who received at least 1 dose of study drug. In the FAS, participants were allocated to the treatment arm corresponding to the study medication that the participant was randomized to (treatment allocation as randomized).

    Subject analysis set title
    Safety Analysis Set (SAF)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The SAF consisted of all randomized participants who received at least 1 study drug dose. In the SAF, participants were allocated to the treatment arm corresponding to study drug first administered (fidaxomicin or vancomycin), even if it differed from the treatment randomized to.

    Primary: Percentage of Participants with Confirmed Clinical Response (CCR) at End of Treatment (EOT) +2 Days

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    End point title
    Percentage of Participants with Confirmed Clinical Response (CCR) at End of Treatment (EOT) +2 Days
    End point description
    Initial clinical response (ICR) for ages from birth to < 2 years was defined as absence of watery diarrhea for 2 consecutive treatment days, remaining well until study drug discontinuation. ICR for ages ≥ 2 years to < 18 years was defined as improvement in number and character of bowel movements as determined by < 3 unformed bowel movements (UBMs) per day for 2 consecutive treatment days, remaining well until study drug discontinuation. CCR was defined for both age groups as not requiring further CDAD therapy within 2 days after study drug completion, and was reported with a positive (Yes) or negative (No) outcome. Resolution of diarrhea was assessed during interviews of participant/parent/legal guardian, supplemented by review of personal records (if hospitalized) and checked for presence of watery diarrhea (ages from birth to < 2 years) or number of UBMs (for ages ≥ 2 years to < 18 years). The analysis population consisted of the FAS.
    End point type
    Primary
    End point timeframe
    Up to day 12
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    98
    44
    Units: percentage of participants
        number (confidence interval 95%)
    77.6 (68.0 to 85.4)
    70.5 (54.8 to 83.2)
    Statistical analysis title
    Adjusted Difference of CCR at EOT + 2 Days
    Statistical analysis description
    Adjusted treatment difference of proportions was calculated using a stratified Cochran-Mantel-Haenszel (CMH) method. Newcombe 95% confidence intervals (CIs) presented for adjusted treatment difference.
    Comparison groups
    Fidaxomicin v Vancomycin
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    adjusted treatment difference
    Point estimate
    7.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.4
         upper limit
    23.9

    Secondary: Percentage of Participants with Sustained Clinical Response (SCR) at EOT +9 Days

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    End point title
    Percentage of Participants with Sustained Clinical Response (SCR) at EOT +9 Days
    End point description
    SCR at EOT + 9 days was defined as CCR (EOT + 2 days) without CDAD recurrence until assessment at EOT +9 days during the follow-up period. Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic Clostridium difficile (C. difficile) in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. FAS population (participants with CCR at EOT +2 days).
    End point type
    Secondary
    End point timeframe
    Up to day 19
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    76
    31
    Units: percentage of participants
        number (confidence interval 95%)
    94.7 (87.1 to 98.5)
    77.4 (58.9 to 90.4)
    Statistical analysis title
    Adjusted Difference of SCR at EOT +9 days
    Statistical analysis description
    Adjusted treatment difference of proportions was calculated using a stratified CMH method. Newcombe 95% CIs presented for adjusted treatment difference.
    Comparison groups
    Fidaxomicin v Vancomycin
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    adjusted treatment difference
    Point estimate
    16.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.8
         upper limit
    34.2

    Secondary: Percentage of Participants with Global Cure (GC) at EOT +9 Days

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    End point title
    Percentage of Participants with Global Cure (GC) at EOT +9 Days
    End point description
    GC was reported as a positive (Yes) or negative (No) outcome and was calculated using SCR and ICR/CCR values according to the following conditions: ● if ICR/CCR=Yes and SCR=Yes, then Global Cure was Yes. ● if ICR/CCR=Yes and SCR =No, then Global Cure was No. ● if ICR/CCR=No (SCR not assessed), then Global Cure was No. ● if ICR/CCR=Missing (SCR not assessed), then Global Cure was set to No. No multiple imputation method (MI) was used for global cure at EOT + 9 days. The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    Up to day 19
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    98
    44
    Units: percentage of participants
        number (confidence interval 95%)
    75.5 (65.8 to 83.6)
    54.5 (38.8 to 69.6)
    Statistical analysis title
    Adjusted Difference of GC at EOT +9 days
    Statistical analysis description
    Adjusted treatment difference of rates was calculated using a stratified CMH method. Newcombe 95% CIs presented for adjusted treatment difference.
    Comparison groups
    Fidaxomicin v Vancomycin
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    adjusted treatment difference
    Point estimate
    21.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.5
         upper limit
    37.7

    Secondary: Percentage of Participants with Recurrence of CDAD at EOT +9 Days

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    End point title
    Percentage of Participants with Recurrence of CDAD at EOT +9 Days
    End point description
    Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. The analysis population consisted of the FAS (participants with CCR at EOT +2 days).
    End point type
    Secondary
    End point timeframe
    Up to day 19
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    76
    31
    Units: percentage of participants
        number (confidence interval 95%)
    5.3 (1.5 to 12.9)
    22.6 (9.6 to 41.1)
    Statistical analysis title
    Adjusted Diff. of CDAD Recurrence at EOT +9 days
    Statistical analysis description
    Adjusted treatment difference of proportions was calculated using a stratified CMH method. Newcombe 95% CIs presented for adjusted treatment difference.
    Comparison groups
    Fidaxomicin v Vancomycin
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    adjusted treatment difference
    Point estimate
    -16.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -34.2
         upper limit
    -1.8

    Secondary: Percentage of Participants with SCR at EOT +16 Days

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    End point title
    Percentage of Participants with SCR at EOT +16 Days
    End point description
    SCR at EOT + 16 days was defined as CCR (EOT + 2 days) without CDAD recurrence until assessment at EOT + 16 days during the follow-up period. Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. The analysis population consisted of the FAS (participants with CCR at EOT +2 days).
    End point type
    Secondary
    End point timeframe
    Up to day 26
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    76
    31
    Units: percentage of participants
        number (confidence interval 95%)
    89.5 (80.3 to 95.3)
    71.0 (52.0 to 85.8)
    Statistical analysis title
    Adjusted Difference of SCR at EOT +16 days
    Statistical analysis description
    Adjusted treatment difference of proportions was calculated using a stratified CMH method. Newcombe 95% CIs presented for adjusted treatment difference.
    Comparison groups
    Fidaxomicin v Vancomycin
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    adjusted treatment difference
    Point estimate
    17.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.9
         upper limit
    35.6

    Secondary: Percentage of Participants with GC at EOT +16 Days

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    End point title
    Percentage of Participants with GC at EOT +16 Days
    End point description
    GC was reported as a positive (Yes) or negative (No) outcome and was calculated using SCR and ICR/CCR values according to the following conditions: ● if ICR/CCR=Yes and SCR=Yes, then Global Cure was Yes. ● if ICR/CCR=Yes and SCR =No, then Global Cure was No. ● if ICR/CCR=No (SCR not assessed), then Global Cure was No. ● if ICR/CCR=Missing (SCR not assessed), then Global Cure was set to No. No multiple imputation method (MI) was used for global cure at EOT + 16 days. The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    Up to day 26
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    98
    44
    Units: percentage of participants
        number (confidence interval 95%)
    71.4 (61.4 to 80.1)
    52.3 (36.7 to 67.5)
    Statistical analysis title
    Adjusted Difference of GC at EOT +16 days
    Statistical analysis description
    Adjusted treatment difference of rates was calculated using a stratified CMH method. Newcombe 95% CIs presented for adjusted treatment difference.
    Comparison groups
    Fidaxomicin v Vancomycin
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    adjusted treatment difference
    Point estimate
    19.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.3
         upper limit
    35.9

    Secondary: Percentage of Participants with Recurrence of CDAD at EOT +16 Days

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    End point title
    Percentage of Participants with Recurrence of CDAD at EOT +16 Days
    End point description
    Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. The analysis population consisted of the FAS (participants with CCR at EOT +2 days).
    End point type
    Secondary
    End point timeframe
    Up to day 26
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    76
    31
    Units: percentage of participants
        number (confidence interval 95%)
    7.9 (3.0 to 16.4)
    25.8 (11.9 to 44.6)
    Statistical analysis title
    Adjusted Diff. of CDAD Recurrence at EOT +16 days
    Statistical analysis description
    Adjusted treatment difference of proportions was calculated using a stratified CMH method. Newcombe 95% CIs presented for adjusted treatment difference.
    Comparison groups
    Fidaxomicin v Vancomycin
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    adjusted treatment difference
    Point estimate
    -17.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -35.6
         upper limit
    -1.9

    Secondary: Percentage of Participants with SCR at EOT +23 Days

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    End point title
    Percentage of Participants with SCR at EOT +23 Days
    End point description
    SCR at EOT + 23 days was defined as CCR (EOT + 2 days) without CDAD recurrence until assessment at EOT + 16 days during the follow-up period. Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. The analysis population consisted of the FAS (participants with CCR at EOT +2 days).
    End point type
    Secondary
    End point timeframe
    Up to day 33
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    76
    31
    Units: percentage of participants
        number (confidence interval 95%)
    85.5 (75.6 to 92.5)
    71.0 (52.0 to 85.8)
    Statistical analysis title
    Adjusted Difference of SCR at EOT +23 days
    Statistical analysis description
    Adjusted treatment difference of proportions was calculated using a stratified CMH method. Newcombe 95% CIs presented for adjusted treatment difference.
    Comparison groups
    Fidaxomicin v Vancomycin
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    adjusted treatment difference
    Point estimate
    15.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    34.5

    Secondary: Percentage of Participants with GC at EOT +23 Days

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    End point title
    Percentage of Participants with GC at EOT +23 Days
    End point description
    GC was reported as a positive (Yes) or negative (No) outcome and was calculated using SCR and ICR/CCR values according to the following conditions: ● if ICR/CCR=Yes and SCR=Yes, then Global Cure was Yes. ● if ICR/CCR=Yes and SCR =No, then Global Cure was No. ● if ICR/CCR=No (SCR not assessed), then Global Cure was No. ● if ICR/CCR=Missing (SCR not assessed), then Global Cure was set to No. No multiple imputation method (MI) was used for global cure at EOT + 23 days. The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    Up to day 33
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    98
    44
    Units: percentage of participants
        number (confidence interval 95%)
    68.4 (58.2 to 77.4)
    50.0 (34.6 to 65.4)
    Statistical analysis title
    Adjusted Difference of GC at EOT +23 days
    Statistical analysis description
    Adjusted treatment difference of rates was calculated using a stratified CMH method. Newcombe 95% CIs presented for adjusted treatment difference.
    Comparison groups
    Fidaxomicin v Vancomycin
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    adjusted treatment difference
    Point estimate
    18.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.5
         upper limit
    35.3

    Secondary: Percentage of Participants with Recurrence of CDAD at EOT +23 Days

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    End point title
    Percentage of Participants with Recurrence of CDAD at EOT +23 Days
    End point description
    Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. The analysis population consisted of the FAS (participants with CCR at EOT +2 days).
    End point type
    Secondary
    End point timeframe
    Up to day 33
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    76
    31
    Units: percentage of participants
        number (confidence interval 95%)
    11.8 (5.6 to 21.3)
    29.0 (14.2 to 48.0)
    Statistical analysis title
    Adjusted Diff. of CDAD Recurrence at EOT +23 days
    Statistical analysis description
    Adjusted treatment difference of proportions was calculated using a stratified CMH method. Newcombe 95% CIs presented for adjusted treatment difference.
    Comparison groups
    Fidaxomicin v Vancomycin
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    adjusted treatment difference
    Point estimate
    -15.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -34.5
         upper limit
    0.5

    Secondary: Percentage of Participants with SCR at End of Study (EOS) (EOT +30 Days)

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    End point title
    Percentage of Participants with SCR at End of Study (EOS) (EOT +30 Days)
    End point description
    SCR at EOS was defined as CCR (EOT + 2 days) without CDAD recurrence until assessment at EOS (EOT + 30 days) during the follow-up period. Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. The analysis population consisted of the FAS (participants with CCR at EOT +2 days).
    End point type
    Secondary
    End point timeframe
    Up to day 40
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    76
    31
    Units: percentage of participants
        number (confidence interval 95%)
    85.5 (75.6 to 92.5)
    71.0 (52.0 to 85.8)
    Statistical analysis title
    Adjusted Difference of SCR at EOS (EOT +30 days)
    Statistical analysis description
    Adjusted treatment difference of proportions was calculated using a stratified CMH method. Newcombe 95% CIs presented for adjusted treatment difference.
    Comparison groups
    Fidaxomicin v Vancomycin
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    adjusted treatment difference
    Point estimate
    15.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    34.5

    Secondary: Percentage of Participants with GC at EOS (EOT +30 Days)

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    End point title
    Percentage of Participants with GC at EOS (EOT +30 Days)
    End point description
    GC was reported as a positive (Yes) or negative (No) outcome and was calculated using SCR and ICR/CCR values according to the following conditions: ● if ICR/CCR=Yes and SCR=Yes, then Global Cure was Yes. ● if ICR/CCR=Yes and SCR =No, then Global Cure was No. ● if ICR/CCR=No (SCR not assessed), then Global Cure was No. ● if ICR/CCR=Missing (SCR not assessed), then Global Cure was set to No. Global Cure at EOT +30 days was derived using MI in case ICR/CCR=Missing (SCR not assessed) following Rubin’s multiple imputation method. The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    Up to day 40
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    98
    44
    Units: percentage of participants
        number (confidence interval 95%)
    68.4 (58.2 to 77.4)
    50.0 (34.6 to 65.4)
    Statistical analysis title
    Adjusted Difference of GC at EOS (EOT +30 days)
    Statistical analysis description
    Adjusted treatment difference of rates was calculated using a stratified CMH method. Newcombe 95% CIs presented for adjusted treatment difference.
    Comparison groups
    Fidaxomicin v Vancomycin
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    adjusted treatment difference
    Point estimate
    18.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.5
         upper limit
    35.3

    Secondary: Percentage of Participants with Recurrence of CDAD at EOS (EOT +30 Days)

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    End point title
    Percentage of Participants with Recurrence of CDAD at EOS (EOT +30 Days)
    End point description
    Recurrence for ages from birth to < 2 years was defined as re-establishment of watery diarrhea after CCR to an extent that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. Recurrence for ages ≥ 2 years < 18 years was defined as re-establishment of diarrhea after CCR to an extent (as measured by the frequency of UBMs) that was greater than that noted on the last day of study drug with positive direct or indirect testing for the presence of toxigenic C. difficile in stool and that, in the investigator's opinion, required retreatment with CDAD anti-infective therapy. The analysis population consisted of the FAS (participants with CCR at EOT +2 days).
    End point type
    Secondary
    End point timeframe
    Up to day 40
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    76
    31
    Units: percentage of participants
        number (confidence interval 95%)
    11.8 (5.6 to 21.3)
    29.0 (14.2 to 48.0)
    Statistical analysis title
    Adj. Diff. of CDAD Recurrence at EOS/EOT +30 days
    Statistical analysis description
    Adjusted treatment difference of proportions was calculated using a stratified CMH method. Newcombe 95% CIs presented for adjusted treatment difference.
    Comparison groups
    Fidaxomicin v Vancomycin
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    adjusted treatment difference
    Point estimate
    -15.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -34.5
         upper limit
    0.5

    Secondary: Time to Resolution of Diarrhea (TTROD)

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    End point title
    Time to Resolution of Diarrhea (TTROD)
    End point description
    TTROD for ages from birth < 2 years was defined as time elapsing (hours rounded up from minutes > 30) from treatment start (time of first study drug dose) to diarrhea resolution (time of last episode of watery diarrhea the day prior to the first of 2 consecutive days without watery diarrhea sustained through EOT). TTROD for ages ≥ 2 years to < 18 years was defined as time elapsing (hours rounded up from minutes > 30) from treatment start (time of first dose) to diarrhea resolution (time of the last UBM the day prior to the first of 2 consecutive days of < 3 UBMs sustained through EOT). TTROD by Kaplan-Meier Method. Those who completed treatment but did not show diarrhea resolution until EOT were censored at Day 10/240 hours. Those who did not complete treatment, discontinued earlier but did not show diarrhea resolution until disc. day were censored at disc. (days converted to hours). Those whose diarrhea did not continue after first dose were included with a TTROD of 1 hour. FAS.
    End point type
    Secondary
    End point timeframe
    Up to day 10
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    98
    44
    Units: hours
        median (confidence interval 95%)
    58 (29.0 to 122.0)
    97 (42.0 to 146.0)
    Statistical analysis title
    Time to resolution of diarrhea
    Comparison groups
    Fidaxomicin v Vancomycin
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.579
    Method
    Logrank
    Confidence interval

    Secondary: Time to Recurrence of CDAD for Participants with CCR at EOT +2 Days

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    End point title
    Time to Recurrence of CDAD for Participants with CCR at EOT +2 Days
    End point description
    Time to recurrence was defined as the time (days) from CCR until the onset of recurrence. Time to recurrence of CDAD by Kaplan-Meier Method. Data for 95% CI was not evaluable due to insufficient number of participants with events. Data not evaluable denoted as "99999." Although median time was evaluable (25 days for the fidaxomicin arm and 26 days for the vancomycin arm) "99999" was entered to bypass system validation error, since 95% CI was not evaluable and system requires "99999" to be entered for data not available (the median values are not between the low and high values of "99999". The analysis population consisted of the FAS (participants with CCR at EOT +2 days). Participants with CCR at EOT+2 days, who completed the follow-up period but did not experience a recurrence of CDAD were censored at EOT+30 days and those who did not complete the follow-up period and discontinued during this period and did not experience a recurrence of CDAD were censored at day of discontinuation.
    End point type
    Secondary
    End point timeframe
    Up to day 40
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    76
    31
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Time to recurrence of CDAD
    Comparison groups
    Fidaxomicin v Vancomycin
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.023
    Method
    Logrank
    Confidence interval

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    Number of Participants with Adverse Events (AEs)
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a study drug or who had undergone study procedures which did not necessarily have a causal relationship with this treatment. This included abnormal laboratory tests, vital signs, electrocardiogram data or physical examinations that were defined as AEs if the abnormality induced clinical signs or symptoms, required active intervention, interruption or discontinuation of study drug or was clinically significant in the investigator's opinion. The following standard with 3 grades was used to measure the severity of AEs, including abnormal clinical laboratory values: ● Mild: No disruption of normal daily activities ● Moderate: Affected normal daily activities ● Severe: Inability to perform daily activities. A treatment-emergent adverse event (TEAE) was defined as an AE observed after starting administration of the test drug/comparative drug. The analysis population consisted of the SAF.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug administration up to 30 days after EOT (up to day 40)
    End point values
    Fidaxomicin Vancomycin
    Number of subjects analysed
    98
    44
    Units: participants
        TEAE
    72
    33
        Drug-related TEAE
    7
    5
        Serious TEAE
    24
    12
        Drug-related Serious TEAE
    0
    0
        Moderate TEAE
    39
    14
        Drug-related Moderate TEAE
    4
    1
        Mild TEAE
    56
    30
        Drug-related Mild TEAE
    3
    4
        TEAE Leading to Death
    3
    0
        Drug-related TEAE Leading to Death
    0
    0
        TEAE leading to Withdrawal of Treatment (Tx)
    1
    1
        Drug-related TEAE Leading to Withdrawal of Tx
    0
    0
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Fidaxomicin

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    End point title
    Plasma Concentrations of Fidaxomicin
    End point description
    Drug concentration was derived from the blood samples collected. The analysis population consisted of the pharmacokinetics analysis set (PKAS). The PKAS consisted of all participants randomized to fidaxomicin, having received at least 1 dose of fidaxomicin and having at least 1 valid measurement of plasma concentration or fecal concentration of fidaxomicin or its main metabolite OP-1118. N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Within 30 minutes predose and 1 to 5 hours postdose taken between day 5 and day 10
    End point values
    Fidaxomin all formulations Fidaxomicin oral suspension Fidaxomicin tablets
    Number of subjects analysed
    98
    67
    31
    Units: ng/mL
    arithmetic mean (standard deviation)
        Predose (Arm 1 N=82, Arm 2 N=55, Arm 3 N=27)
    20.17 ± 40.16
    15.26 ± 20.43
    30.16 ± 63.27
        Postdose (Arm 1 N=81, Arm 2 N=53, Arm 3 N=28)
    39.41 ± 62.15
    34.60 ± 57.79
    48.53 ± 69.85
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Metabolite OP-1118

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    End point title
    Plasma Concentrations of Metabolite OP-1118
    End point description
    Drug concentration was derived from the blood samples collected. The analysis population consisted of the PKAS. N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Within 30 minutes predose and 1 to 5 hours postdose taken between day 5 and day 10
    End point values
    Fidaxomin all formulations Fidaxomicin oral suspension Fidaxomicin tablets
    Number of subjects analysed
    98
    67
    31
    Units: ng/mL
    arithmetic mean (standard deviation)
        Predose (Arm 1 N=82, Arm 2 N=55, Arm 3 N=27)
    63.04 ± 171.97
    42.18 ± 76.76
    105.54 ± 277.67
        Postdose (Arm 1 N=81, Arm 2 N=53, Arm 3 N=28)
    116.64 ± 259.10
    102.38 ± 245.19
    143.63 ± 286.31
    No statistical analyses for this end point

    Secondary: Metabolite-to-Parent Ratio (MPRconc)

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    End point title
    Metabolite-to-Parent Ratio (MPRconc)
    End point description
    Drug concentration was derived from the blood samples collected. The analysis population consisted of the PKAS. N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Within 30 minutes predose and 1 to 5 hours postdose taken between day 5 and day 10
    End point values
    Fidaxomin all formulations Fidaxomicin oral suspension Fidaxomicin tablets
    Number of subjects analysed
    98
    67
    31
    Units: ratio
    arithmetic mean (standard deviation)
        Predose (Arm 1 N=82, Arm 2 N=55, Arm 3 N=27)
    3.18 ± 1.42
    3.24 ± 1.46
    3.05 ± 1.35
        Postdose (Arm 1 N=81, Arm 2 N=53, Arm 3 N=28)
    2.86 ± 1.18
    2.95 ± 1.23
    2.69 ± 1.06
    No statistical analyses for this end point

    Secondary: Fecal Concentrations of Fidaxomicin

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    End point title
    Fecal Concentrations of Fidaxomicin
    End point description
    Drug concentration was derived from the stool samples collected. The analysis population consisted of the PKAS.
    End point type
    Secondary
    End point timeframe
    Within 24 hours of a dose taken between day 5 and day 10
    End point values
    Fidaxomin all formulations Fidaxomicin oral suspension Fidaxomicin tablets
    Number of subjects analysed
    74
    47
    27
    Units: ng/mL
    arithmetic mean (standard deviation)
        Postdose
    2685.56 ± 2476.92
    2969.87 ± 2713.58
    2190.63 ± 1948.68
    No statistical analyses for this end point

    Secondary: Fecal Concentrations of Metabolite OP-1118

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    End point title
    Fecal Concentrations of Metabolite OP-1118
    End point description
    Drug concentration was derived from the stool samples collected. The analysis population consisted of the PKAS.
    End point type
    Secondary
    End point timeframe
    Within 24 hours of a dose taken between day 5 and day 10
    End point values
    Fidaxomin all formulations Fidaxomicin oral suspension Fidaxomicin tablets
    Number of subjects analysed
    73
    46
    27
    Units: ng/mL
        arithmetic mean (standard deviation)
    889.23 ± 817.83
    789.15 ± 728.58
    1059.73 ± 941.04
    No statistical analyses for this end point

    Secondary: MPRconc Within 24 Hours of a Dose

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    End point title
    MPRconc Within 24 Hours of a Dose
    End point description
    Drug concentration was derived from the stool samples collected. The analysis population consisted of the PKAS.
    End point type
    Secondary
    End point timeframe
    Within 24 hours of a dose taken between day 5 and day 10
    End point values
    Fidaxomin all formulations Fidaxomicin oral suspension Fidaxomicin tablets
    Number of subjects analysed
    72
    45
    27
    Units: ratio
    arithmetic mean (standard deviation)
        Postdose
    0.43 ± 0.31
    0.32 ± 0.19
    0.63 ± 0.38
    No statistical analyses for this end point

    Secondary: Acceptance of Formulation (Palatability Assessment) in All Participants at First Administration of Study Drug and at Day 7

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    End point title
    Acceptance of Formulation (Palatability Assessment) in All Participants at First Administration of Study Drug and at Day 7
    End point description
    Acceptance of formulation was evaluated in all participants who received fidaxomicin oral suspension and vancomycin oral liquid (i.e., participants from birth to =< 6 years and participants > 6 years unable to swallow tablets) by means of a five-point rating scale (awful, poor, fair, good, excellent) by unblinded staff if hospitalized, and by the participant/parents/legal guardian when at home. The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    Days 1 and 7
    End point values
    Fidaxomicin oral suspension Vancomycin oral liquid
    Number of subjects analysed
    67
    30
    Units: participants
        Day 1 Awful
    4
    5
        Day 1 Poor
    6
    3
        Day 1 Fair
    13
    6
        Day 1 Good
    19
    7
        Day 1 Excellent
    13
    4
        Day 1 Missing
    12
    5
        Day 7 Awful
    2
    3
        Day 7 Poor
    5
    5
        Day 7 Fair
    8
    5
        Day 7 Good
    21
    9
        Day 7 Excellent
    16
    3
        Day 7 Missing
    15
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug administration up to 30 days after EOT (up to day 40)
    Adverse event reporting additional description
    The total number of deaths (all causes) includes deaths reported after time frame above.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Fidaxomicin
    Reporting group description
    Participants from birth to < 6 years of age received weight based doses of fidaxomicin oral suspension (32 mg/kg/day with a maximum dose of 400 mg/day, divided in 2 doses) 2 times daily for 10 days. Participants aged ≥ 6 years to < 18 years of age received a 200 mg fidaxomicin tablet 2 times daily for 10 days.

    Reporting group title
    Vancomycin
    Reporting group description
    Participants from birth to < 6 years of age received weight based doses of vancomycin oral liquid (40 mg/kg/day with a maximum dose of 500 mg/day divided in 4 doses) 4 times daily for 10 days. Participants aged ≥ 6 years to < 18 years of age received a 125 mg vancomycin capsule 4 times daily for 10 days.

    Serious adverse events
    Fidaxomicin Vancomycin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 98 (24.49%)
    12 / 44 (27.27%)
         number of deaths (all causes)
    3
    2
         number of deaths resulting from adverse events
    3
    0
    Surgical and medical procedures
    Radiotherapy
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Leukaemia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant ascites
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food allergy
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 98 (2.04%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Heart rate irregular
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Mitochondrial encephalomyopathy
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 98 (3.06%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (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
    Renal failure
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    2 / 98 (2.04%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 98 (2.04%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial diarrhoea
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal sepsis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex meningoencephalitis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scedosporium infection
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 98 (2.04%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Fidaxomicin Vancomycin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 98 (36.73%)
    21 / 44 (47.73%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 98 (8.16%)
    0 / 44 (0.00%)
         occurrences all number
    11
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    11 / 98 (11.22%)
    8 / 44 (18.18%)
         occurrences all number
    18
    11
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 98 (5.10%)
    9 / 44 (20.45%)
         occurrences all number
    6
    11
    Constipation
         subjects affected / exposed
    5 / 98 (5.10%)
    1 / 44 (2.27%)
         occurrences all number
    6
    1
    Vomiting
         subjects affected / exposed
    7 / 98 (7.14%)
    6 / 44 (13.64%)
         occurrences all number
    8
    8
    Diarrhoea
         subjects affected / exposed
    7 / 98 (7.14%)
    4 / 44 (9.09%)
         occurrences all number
    7
    5
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 98 (3.06%)
    3 / 44 (6.82%)
         occurrences all number
    3
    3
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    3 / 98 (3.06%)
    3 / 44 (6.82%)
         occurrences all number
    3
    3

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Nov 2014
    The changes include: ● Throughout the protocol, the age ranges '< 6 months of age' were changed to 'from birth'. Nonsubstantial changes were made to the protocol: ● To update the contract research organization (CRO) contact for reporting SAEs and contact details of clinical research contact; ● To add text on the coadministration of P-glycoprotein inhibitor to the introduction; ● To add the term palatability to study objectives; ● To update the number of study sites to approximately 65 to 80 sites; ● To move palatability from exploratory endpoint to secondary endpoint, and replace cultures with samples in the exploratory microbiology endpoint; ● To update statistical methodology (several sections); ● To update the schedule of assessments, changing 'Follow-up visit' to 'Follow-up TC'; ● To update the timeframe for positive detection of CDAD, changing it from within 48 hours to within 72 hours prior to randomization; ● To update the risk-benefit assessment, adding text on children < 6 months of age and on hypersensitivity reactions; ● To add weight-based dosing instruction of the fidaxomicin oral suspension and the vancomycin oral liquid; ● To update the specified AEs of interest and add lack of efficacy to the special situation events; and ● To include edits for consistency and other minor administrative-type corrections.
    21 Jul 2015
    The changes include: ● Inclusion criterion No. 2 was amended to specify that in the US, subjects could only be included if aged ≥ 6 months to < 18 years. Nonsubstantial changes were made to the protocol: ● To update safety reporting, removing reporting to delegated CRO only for North American sites; ● To update contact details for the clinical research contact; ● To extend the planned study period based on expected recruitment rate; ● To update/revise study design to investigate subjects from birth instead of ≥ 6 months, with the exception of the US; ● To update/revise study design to administer fidaxomicin tablets to subjects aged ≥ 6 years instead of from birth; ● To update concomitant treatment, including the most recent use of fidaxomicin or any macrolide antibiotic to be recorded in the electronic Case Report Form (eCRF); ● To update discontinuation of individual subjects, updating the terminology in alignment with new process for protocol deviation; ● To include instructional text related to reporting certain events as AEs based on local requirements; and ● To include edits for consistency and other minor administrative-type corrections.

    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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