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    Clinical Trial Results:
    A multi-center, randomized, double-blind study to compare the efficacy and safety of cadazolid versus vancomycin in subjects with Clostridium difficile-associated diarrhea (CDAD)

    Summary
    EudraCT number
    		 2013-002528-17
    Trial protocol
    		 DE   IT   ES   PL   NL  
    Global end of trial date
    24 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Apr 2018
    First version publication date
    07 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-061A301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01987895
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, 4123
    Public contact
    Global Scientific Information, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@its.jnj.com
    Scientific contact
    clinical trial disclosure desk, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether the clinical response after 10-day oral administration of cadazolid was non-inferior to oral vancomycin in subjects with Clostridium difficile-associated diarrhea (CDAD)
    Protection of trial subjects
    The clinical trial was designed and conducted in accordance with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations, including the European Directive 2001/20/EC, the US CFR Title 21 (adapt to the countries where the trial was conducted), and with the ethical principles laid down in the Declaration of Helsinki
    Background therapy
    		 -
    Evidence for comparator
    		 The comparator, vancomycin, is approved in Europe and in the US for the treatment of mild–moderate CDAD
    Actual start date of recruitment
    28 Mar 2014
    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
    United States: 213
    Country: Number of subjects enrolled
    Canada: 173
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 35
    Country: Number of subjects enrolled
    Romania: 102
    Country: Number of subjects enrolled
    Spain: 62
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Peru: 1
    Worldwide total number of subjects
    632
    EEA total number of subjects
    234
    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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    389
    From 65 to 84 years
    222
    85 years and over
    21

    Subject disposition

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    Recruitment
    Recruitment details
    		 904 patients at 70 sites in 12 countries were screened, among whom 632 were enrolled in the IMPACT 1 trial at 64 sites located in North & South America, Europe and Australia.

    Pre-assignment
    Screening details
    		 Screening assessments were to be performed up to a maximum of 48 h, from the signature of the informed consent form to randomization

    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, Data analyst, Carer, Assessor
    Blinding implementation details
    The sponsor staff (except Global Drug Safety in case of SUSAR) and CRO staff (except people responsible for safety report distribution or for bioanalytical analyses of cadazolid) remained blinded to the treatment until unblinding after study closure

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cadazolid
    Arm description
    		 Subjects with Clostridium difficile-associated diarrhea (CDAD) received oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times a day (qid) for 10 days. Subjects were followed up for 30 days after the last dose of cadazolid. Subjects who had a first recurrence of CDAD during the follow-up period were offered to enter a re-treatment extension period with cadazolid (10 day of cadazolid + 30-day follow up)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cadazolid
    Investigational medicinal product code
    ACT-179811
    Other name
    Pharmaceutical forms
    Granules for oral solution in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    granules to be reconstituted as a suspension prior to oral administration, supplied at a dose of 250 mg

    Investigational medicinal product name
    vancomycin-matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Capsule identical to vancomycin-capsule but without active substance

    Arm title
    		 Vancomycin
    Arm description
    		 Subjects with CDAD received oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days. Subjects were followed up for 30 day after the last dose of vancomycin. Subjects who had a first recurrence of CDAD during the follow-up period were offered to enter a re-treatment extension period with cadazolid (10 day of cadazolid + 30-day follow up)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cadazolid-matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules for oral solution in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    granules to be reconstituted as a suspension prior to oral administration, without active substance

    Investigational medicinal product name
    Vancomycin
    Investigational medicinal product code
    Other name
    Vancocin®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Each capsule contains 125 mg of vancomycin

    Number of subjects in period 1
    		Cadazolid Vancomycin
    Started
    306
    326
    Completed
    276
    296
    Not completed
    30
    30
         Adverse event, serious fatal
    7
    7
         Consent withdrawn by subject
    12
    7
         Physician decision
    8
    10
         Lost to follow-up
    3
    5
         randomized before giving IC
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cadazolid
    Reporting group description
    		 Subjects with Clostridium difficile-associated diarrhea (CDAD) received oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times a day (qid) for 10 days. Subjects were followed up for 30 days after the last dose of cadazolid. Subjects who had a first recurrence of CDAD during the follow-up period were offered to enter a re-treatment extension period with cadazolid (10 day of cadazolid + 30-day follow up)

    Reporting group title
    Vancomycin
    Reporting group description
    		 Subjects with CDAD received oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days. Subjects were followed up for 30 day after the last dose of vancomycin. Subjects who had a first recurrence of CDAD during the follow-up period were offered to enter a re-treatment extension period with cadazolid (10 day of cadazolid + 30-day follow up)

    Reporting group values
    		 Cadazolid Vancomycin Total
    Number of subjects
    		 306 326
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.6 ( 17.2 ) 55.6 ( 18.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 186 198 384
        Male
    		 120 128 248
    Subject analysis sets

    Subject analysis set title
    Intent-to-treat set (mITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects who have received at least one dose of study treatment and had a confirmed diagnosis of CDAD

    Subject analysis set title
    Per protocol set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects from the mITT and without protocol deviations that might affect the evaluation of the effect of the study drug on the primary variable.

    Subject analysis set title
    Safety set (SS)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized subjects who received at least one dose of study treatment and analyzed based on the actual treatment received

    Subject analysis sets values
    		 Intent-to-treat set (mITT) Per protocol set (PPS) Safety set (SS)
    Number of subjects
    620
    570
    626
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    56.5 ( 17.6 )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    378
        Male
    242

    End points

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    End points reporting groups
    Reporting group title
    Cadazolid
    Reporting group description
    		 Subjects with Clostridium difficile-associated diarrhea (CDAD) received oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times a day (qid) for 10 days. Subjects were followed up for 30 days after the last dose of cadazolid. Subjects who had a first recurrence of CDAD during the follow-up period were offered to enter a re-treatment extension period with cadazolid (10 day of cadazolid + 30-day follow up)

    Reporting group title
    Vancomycin
    Reporting group description
    		 Subjects with CDAD received oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days. Subjects were followed up for 30 day after the last dose of vancomycin. Subjects who had a first recurrence of CDAD during the follow-up period were offered to enter a re-treatment extension period with cadazolid (10 day of cadazolid + 30-day follow up)

    Subject analysis set title
    Intent-to-treat set (mITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects who have received at least one dose of study treatment and had a confirmed diagnosis of CDAD

    Subject analysis set title
    Per protocol set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects from the mITT and without protocol deviations that might affect the evaluation of the effect of the study drug on the primary variable.

    Subject analysis set title
    Safety set (SS)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized subjects who received at least one dose of study treatment and analyzed based on the actual treatment received

    Primary: Clinical Cure Rate (CCR) in the modified intent-to-treat population

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    End point title
    		 Clinical Cure Rate (CCR) in the modified intent-to-treat population
    End point description
    Clinical Cure (CC) is defined as: • Resolution of Diarrhea (≤ 3 unformed bowel movement per day for at least 2 consecutive days) on study treatment and maintained for 2 days after end-of-treatment (EOT), AND • No additional antimicrobial treatment active against Clostridium difficile-associated diarrhea (CDAD) or fecal microbiota transplant between first dose of study drug and 2 days after EOT. CCR is the percentage of subjects with Clinical Cure. Analyses are performed on two analysis sets. Results on the modified intent-to-treat set (mITT) are reported below.
    End point type
    Primary
    End point timeframe
    Up to Day 12 on average (end-of-treatment + 2 days)
    End point values
    		 Cadazolid Vancomycin
    Number of subjects analysed
    302
    318
    Units: Percentage of participants
    number (confidence interval 95%)
        Percentage of participants
    83.8 (79.2 to 87.5)
    85.2 (80.9 to 88.7)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Vancomycin v Cadazolid
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference between 2 proportions
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.2
         upper limit
    		 4.3
    Notes
    [1] - Non-inferiority of CCR for cadazolid versus vancomycin is demonstrated if the lower limit of the 95% confidence interval (CI) is above –10%. The 95%CI difference in proportion was estimated using the Wilson's score method.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Sensitivity analysis with imputation for a single day with missing UBM data between one day before end-of-treatment (EOT) and 2 days after EOT
    Comparison groups
    Cadazolid v Vancomycin
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Difference between 2 proportions
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.1
         upper limit
    		 3.2
    Notes
    [2] - Non-inferiority of CCR for cadazolid versus vancomycin is demonstrated if the lower limit of the 95% confidence interval (CI) is above –10%. The 95%CI difference in proportion was estimated using the Wilson's score method.

    Primary: Clinical Cure Rate (CCR) in the per-protocol population

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    End point title
    		 Clinical Cure Rate (CCR) in the per-protocol population
    End point description
    Clinical Cure (CC) is defined as: • Resolution of Diarrhea (≤ 3 unformed bowel movement per day for at least 2 consecutive days) on study treatment and maintained for 2 days after end-of-treatment (EOT), AND • No additional antimicrobial treatment active against Clostridium difficile-associated diarrhea (CDAD) or fecal microbiota transplant between first dose of study drug and 2 days after EOT. CCR is the percentage of subjects with Clinical Cure. Analyses are performed on two analysis sets. Results on the per-protocol set (PPS) are reported below.
    End point type
    Primary
    End point timeframe
    Up to Day 12 on average (end-of-treatment + 2 days)
    End point values
    		 Cadazolid Vancomycin
    Number of subjects analysed
    282
    288
    Units: Percentage of participants
    number (confidence interval 95%)
        Percentage of participants
    87.6 (83.2 to 90.9)
    91.7 (87.9 to 94.3)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Vancomycin v Cadazolid
    Number of subjects included in analysis
    570
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Difference between 2 proportions
    Point estimate
    -4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.2
         upper limit
    		 1
    Notes
    [3] - Non-inferiority of CCR for cadazolid versus vancomycin is demonstrated if the lower limit of the 95% confidence interval (CI) is above –10%. The 95%CI difference in proportion was estimated using the Wilson's score method.

    Secondary: Sustained Cure Rate (SCR) in the modified intent-to-treat population

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    End point title
    		 Sustained Cure Rate (SCR) in the modified intent-to-treat population
    End point description
    Sustained Cure is defined for each subject having Clinical Cure and no recurrence. SCR is the percentage of subjects with Sustained Cure. The main analysis is performed on the modified intent-to-treat set (mITT).
    End point type
    Secondary
    End point timeframe
    Between Day 38 and Day 42 on average (end-of-treatment + 28-32 days)
    End point values
    		 Cadazolid Vancomycin
    Number of subjects analysed
    302
    318
    Units: Percentage of participants
    number (confidence interval 95%)
        Percentage of participants
    65.6 (60.0 to 70.7)
    62.3 (56.8 to 67.4)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Cadazolid v Vancomycin
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    Method
    Parameter type
    		 Difference between 2 proportions
    Point estimate
    3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.3
         upper limit
    		 10.8
    Notes
    [4] - Superiority of cadazolid versus vancomycin is demonstrated if the lower limit of the 95% confidence interval (CI) is above zero. The 95%CI difference in proportion was estimated using the Wilson's score method.

    Secondary: Kaplan-Meier estimates for resolution of diarrhea

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    End point title
    		 Kaplan-Meier estimates for resolution of diarrhea
    End point description
    Resolution of Diarrhea (ROD) is defined as no more than 3 unformed bowel movements per day for at least two consecutive days for subjects on study treatment. The Kaplan-Meier estimates (KM estimates) for having an event (ROD) are reported for each time point.
    End point type
    Secondary
    End point timeframe
    Up to Day 10
    End point values
    		 Cadazolid Vancomycin
    Number of subjects analysed
    302
    318
    Units: KM estimate (%)
    number (confidence interval 95%)
        Day 1
    46.7 (41.2 to 52.5)
    45.9 (40.6 to 51.6)
        Day 2
    62.6 (57.2 to 68.0)
    60.7 (55.4 to 66.1)
        Day 3
    69.9 (64.6 to 74.9)
    71.1 (66.0 to 76.0)
        Day 4
    72.8 (67.7 to 77.7)
    77.7 (73.0 to 82.1)
        Day 5
    77.8 (73.0 to 82.3)
    80.2 (75.6 to 84.4)
        Day 6
    81.1 (76.5 to 85.3)
    81.8 (77.3 to 85.8)
        Day 7
    82.5 (78.0 to 86.5)
    84.6 (80.4 to 88.3)
        Day 8
    83.4 (79.0 to 87.4)
    85.2 (81.1 to 88.9)
        Day 9
    83.8 (79.4 to 87.7)
    85.2 (81.1 to 88.9)
        Day 10
    83.8 (79.4 to 87.7)
    85.2 (81.1 to 88.9)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Vancomycin v Cadazolid
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6016 [5]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.14
    Notes
    [5] - two-sided p-value (alpha 5%) based on log-rank test stratified by first occurrence / first recurrence and geographical region.

    Secondary: Change from baseline to Day 3 in Clostridium difficile infection (CDI) daily symptoms Patient-Reported Outcome (CDI-DaySyms PRO) domain scores

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    End point title
    		 Change from baseline to Day 3 in Clostridium difficile infection (CDI) daily symptoms Patient-Reported Outcome (CDI-DaySyms PRO) domain scores
    End point description
    CDI-DaySyms PRO is a questionnaire assessing 10 symptoms relevant to subjects with CDAD and grouped into 3 domains: Diarrhea symptoms, Abdominal symptoms and Systemic/Other. The subjects rate the severity of each item as None, Mild, Moderate, Severe or Very severe, converted to numeric scores from 0 to 4, respectively. A decrease in domain score indicates a better outcome.
    End point type
    Secondary
    End point timeframe
    Day 3
    End point values
    		 Cadazolid Vancomycin
    Number of subjects analysed
    246
    260
    Units: LSM Estimates
    least squares mean (confidence interval 95%)
        Diarrhea symptoms
    -1.233 (-1.37 to -1.09)
    -1.235 (-1.37 to -1.10)
        Abdominal symptoms
    -0.623 (-0.74 to -0.51)
    -0.710 (-0.82 to -0.60)
        Other symptoms
    -0.639 (-0.74 to -0.54)
    -0.689 (-0.79 to -0.59)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Comparison of the diarrhea domain scores
    Comparison groups
    Vancomycin v Cadazolid
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9814 [6]
    Method
    		 ANOVA
    Parameter type
    		 Least Square Mean difference
    Point estimate
    0.002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.2
    Notes
    [6] - Two-sided 5% alpha level was used
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Comparison of the abdominal symptoms domain scores
    Comparison groups
    Vancomycin v Cadazolid
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2879 [7]
    Method
    		 ANOVA
    Parameter type
    		 Least Square Mean difference
    Point estimate
    0.087
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.25
    Notes
    [7] - Two-sided 5% alpha level was used
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Comparison of the systemic / other symptoms domain scores
    Comparison groups
    Vancomycin v Cadazolid
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.488 [8]
    Method
    		 ANOVA
    Parameter type
    		 Least Square Mean difference
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.19
    Notes
    [8] - Two-sided 5% alpha level was used

    Other pre-specified: Investigator's assessment of clinical response (ICR) rate at Visit 4 in the modified intent-to-treat population

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    End point title
    		 Investigator's assessment of clinical response (ICR) rate at Visit 4 in the modified intent-to-treat population
    End point description
    ICR rate (%) is the percentage of subjects with clinical response assessed as cured according to the investigator's own judgement. Subjects with missing assessment are considered as not cured for the analysis. ICR rate is used as a supportive measure of the primary efficacy endpoint (CCR). Analyses are performed on two analysis sets. Results on the modified intent-to-treat set (mITT) are reported below.
    End point type
    Other pre-specified
    End point timeframe
    Up to Day 12 on average (up to end-of-treatment + 2 to 4 days)
    End point values
    		 Cadazolid Vancomycin
    Number of subjects analysed
    302
    318
    Units: Percentage of participants
    number (confidence interval 95%)
        Percentage of participants
    89.7 (85.8 to 92.7)
    91.5 (87.9 to 94.1)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Exploratory analysis
    Comparison groups
    Cadazolid v Vancomycin
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    Parameter type
    		 Difference between 2 proportions
    Point estimate
    -1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.5
         upper limit
    		 2.9
    Notes
    [9] - The 95%CI difference in proportion was estimated using the Wilson's score method.

    Other pre-specified: Investigator's assessment of clinical response (ICR) rate at Visit 4 in the per-protocol population

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    End point title
    		 Investigator's assessment of clinical response (ICR) rate at Visit 4 in the per-protocol population
    End point description
    ICR rate (%) is the percentage of subjects with clinical response assessed as cured according to the investigator's own judgement. ICR rate (%) is the percentage of subjects with ICR assessed as cured. Subjects with missing assessment are considered as not cured for the analysis. ICR rate is used as a supportive measure of the primary efficacy endpoint (CCR). Analyses are performed on two analysis sets. Results on the per-protocol set (PPS) are reported below.
    End point type
    Other pre-specified
    End point timeframe
    Up to Day 12 on average (up to end-of-treatment + 2 to 4 days)
    End point values
    		 Cadazolid Vancomycin
    Number of subjects analysed
    282
    288
    Units: Percentage of participants
    number (confidence interval 95%)
        Percentage of participants
    92.2 (88.5 to 94.8)
    94.1 (90.8 to 96.3)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Exploratory analysis
    Comparison groups
    Cadazolid v Vancomycin
    Number of subjects included in analysis
    570
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    Method
    Parameter type
    		 Difference between 2 proportions
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 2.3
    Notes
    [10] - The 95%CI difference in proportion was estimated using the Wilson's score method.

    Other pre-specified: Investigator's assessment of sustained response rate (ISR rate) at Visit 5

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    End point title
    		 Investigator's assessment of sustained response rate (ISR rate) at Visit 5
    End point description
    ISR rate (%) is the percentage of subjects assessed as Sustained Cure at Visit 5, according to the investigator's own judgement. Sustained Cure is defined for each subject having Clinical Cure and no recurrence. Subjects with missing assessment are considered as having ‘Not Sustained Cure’ for the analysis. ISR rate is used as a supportive measure of the secondary efficacy endpoint (SCR). Analyses are performed on the modified intent-to-treat set (mITT).
    End point type
    Other pre-specified
    End point timeframe
    Between Day 38 and Day 42 on average (end-of-treatment + 28 to 32 days)
    End point values
    		 Cadazolid Vancomycin
    Number of subjects analysed
    302
    318
    Units: Percentage of participants
    number (confidence interval 95%)
        Percentage of participants
    73.8 (68.6 to 78.5)
    70.1 (64.9 to 74.9)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Exploratory analysis
    Comparison groups
    Vancomycin v Cadazolid
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    Method
    Parameter type
    		 Difference between 2 proportions
    Point estimate
    3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 10.7
    Notes
    [11] - The 95%CI difference in proportion was estimated using the Wilson's score method.

    Other pre-specified: Sustained Cure Rate (SCR) in the per-protocol population

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    End point title
    		 Sustained Cure Rate (SCR) in the per-protocol population
    End point description
    Sustained Cure is defined for each subject having Clinical Cure and no recurrence. SCR is the percentage of subjects with Sustained Cure. The analyses performed on the modified intent-to- treat set (mITT) are repeated on the per-protocol set (PPS) for sensitivity.
    End point type
    Other pre-specified
    End point timeframe
    Between Day 38 and Day 42 on average (end-of-treatment + 28-32 days)
    End point values
    		 Cadazolid Vancomycin
    Number of subjects analysed
    282
    288
    Units: Percentage of participants
    number (confidence interval 95%)
        Percentage of participants
    68.8 (63.2 to 73.9)
    67.7 (62.1 to 72.8)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Sensitivity analysis
    Comparison groups
    Vancomycin v Cadazolid
    Number of subjects included in analysis
    570
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    Method
    Parameter type
    		 Difference between 2 proportions
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.5
         upper limit
    		 8.7
    Notes
    [12] - The 95%CI difference in proportion was estimated using the Wilson's score method.

    Other pre-specified: Recurrence rate

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    End point title
    		 Recurrence rate
    End point description
    Recurrence is defined as the occurrence of a new episode of diarrhea (> 3 unformed bowel movements on any day between end-of-treatment + 3 days and end-of-treatment + 30 days ) Recurrence rates is the percentage of subjects assessed as having a recurrence out of subjects with Clinical Cure.
    End point type
    Other pre-specified
    End point timeframe
    Between Day 13 and Day 40 on average (from end-of-treatment + 3 days and end-of-treatment + 30 days)
    End point values
    		 Cadazolid Vancomycin
    Number of subjects analysed
    253
    271
    Units: percentage of participants
    number (confidence interval 95%)
        percentage of participants
    15 (11.1 to 19.9)
    21.4 (16.9 to 26.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious and frequent adverse events are reported from study treatment initiation up to Day 17 on average (i.e., 7 days after EOT or study withdrawal) and all-cause mortality up to Day 40 on average (i.e. 28 to 32 days after EOT on average)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Vancomycin
    Reporting group description
    		 322 subjects received at least one dose of vancomycin and were included in the safety analysis. The median duration of treatment with vancomycin was 10 days.

    Reporting group title
    Cadazolid
    Reporting group description
    		 304 subjects received at least one dose of cadazolid and were included in the safety analysis. The median duration of treatment with cadazolid was 10 days.

    Serious adverse events
    		 Vancomycin Cadazolid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 322 (8.07%)
    19 / 304 (6.25%)
         number of deaths (all causes)
    7
    7
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic cancer
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic carcinoma of the bladder
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 322 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (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
    Oedema peripheral
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute chest syndrome
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Anaemia postoperative
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary anastomosis complication
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Megacolon
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal stenosis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (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 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis of male external genital organ
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    8 / 322 (2.48%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Perineal abscess
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         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 / 322 (0.62%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Vancomycin Cadazolid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 322 (15.22%)
    33 / 304 (10.86%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    25 / 322 (7.76%)
    14 / 304 (4.61%)
         occurrences all number
    28
    17
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    22 / 322 (6.83%)
    14 / 304 (4.61%)
         occurrences all number
    24
    16
    Nausea
         subjects affected / exposed
    24 / 322 (7.45%)
    12 / 304 (3.95%)
         occurrences all number
    27
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Dec 2014
    Main reason for amendment: the main analysis of the primary endpoint (Clinical Cure) initially planned to be performed on the per-protocol population will be conducted on both the modified Intent-to-Treat and Per Protocol populations. Further changes include the addition of an emerging hypervirulent Clostridium difficile strain, the addition of endpoints related to susceptibility testing of C. difficile and vancomycin-resistant enterococci, and general clarifications of eligibility criteria and statistical analyses including a modification to the definition of recurrence for analyses of secondary variable sustained cure rate.
    22 Oct 2015
    To remove the interim analysis originally planned after the randomization of 67% of the subjects.

    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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