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    Clinical Trial Results:
    A Phase 2, Randomized, Double-blind, Placebo-controlled, Dose-ranging Study to Assess the Safety and Efficacy of VP 20621 for Prevention of Recurrence of Clostridium difficile Infection (CDI) in Adults Previously Treated for CDI

    Summary
    EudraCT number
    		 2010-020484-20
    Trial protocol
    		 BE   DE   ES  
    Global end of trial date
    11 Jun 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    28 Feb 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20621-200
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01259726
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ViroPharma Incorporated
    Sponsor organisation address
    730 Stockton Drive, Exton, Pennsylvania, United States, 19341
    Public contact
    20621-200 Study Team, ViroPharma Incorporated, 1 610321 6215, VP20621-200@viropharma.com
    Scientific contact
    20621-200 Study Team, ViroPharma Incorporated, 1 610321 6215, VP20621-200@viropharma.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
    11 Jun 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jun 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objectives of this study were to: (1) evaluate the safety and tolerability of VP 20621 dosed orally for up to 14 days in adults previously treated for CDI; (2) characterize the frequency and duration of stool colonization with the VP 20621 strain of Clostridium (C.) difficile; (3) evaluate the efficacy of VP 20621 for prevention of recurrence of CDI; and (4) select a dose regimen of VP 20621 to be used in future studies.
    Protection of trial subjects
    The study was performed in accordance with the ethical principles stated in the Declaration of Helsinki and the International Conference on Harmonization Tripartite Guideline for Good Clinical Practice.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jun 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Canada: 26
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United States: 127
    Worldwide total number of subjects
    173
    EEA total number of subjects
    19
    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)
    106
    From 65 to 84 years
    59
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at a total of 44 investigative sites [United states (US)=33, Canada=4, and Europe=7], and 3 of the 33 US sites did not enroll any subjects (each had 1 screen failure).

    Pre-assignment
    Screening details
    		 Of the 213 subjects formally screened to participate in this study, 40 subjects were screen failures. The most common reason for screen failure was violation of one or more inclusion/exclusion criteria in 29 subjects, followed by withdrawal of consent in 10 subjects, and death of 1 subject during screening period.

    Pre-assignment period milestones
    Number of subjects started
    		 173
    Intermediate milestone: Number of subjects
    Treated: 168
    Number of subjects completed
    		 168

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Feeling poorly: 1
    Reason: Number of subjects
    		 Violation of exclusion criterion: 1
    Reason: Number of subjects
    		 Screen failures: 2
    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo matched to VP 20621 oral liquid once daily from Day 1 to 14.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to VP 20621 oral liquid once daily from Day 1 to 14.

    Arm title
    		 VP 20621 Low Dose and Placebo
    Arm description
    		 VP 20621 oral liquid containing 10^4 purified spores of non-toxigenic Clostridium difficile-strain M3 (NTCD-M3; the dormant form of a live organism) once daily from Day 1 to 7 followed by placebo matched to VP 20621 oral liquid once daily from Day 8 to 14.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VP 20621
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    VP 20621 oral liquid containing 10^4 purified spores of NTCD-M3 once daily from Day 1 to 7.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to VP 20621 oral liquid once daily from Day 8 to 14.

    Arm title
    		 VP 20621 High Dose and Placebo
    Arm description
    		 VP 20621 oral liquid containing 10^7 purified spores of NTCD-M3 once daily from Day 1 to 7 followed by placebo matched to VP 20621 oral liquid once daily from Day 8 to 14.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VP 20621
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    VP 20621 oral liquid containing 10^7 purified spores of NTCD-M3 once daily from Day 1 to 7.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to VP 20621 oral liquid once daily from Day 8 to 14.

    Arm title
    		 VP 20621 High Dose
    Arm description
    		 VP 20621 oral liquid containing 10^7 purified spores of NTCD-M3 once daily from Day 1 to 14.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VP 20621
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    VP 20621 oral liquid containing 10^7 purified spores of NTCD-M3 once daily from Day 1 to 14.

    Number of subjects in period 1 [1]
    		Placebo VP 20621 Low Dose and Placebo VP 20621 High Dose and Placebo VP 20621 High Dose
    Started
    43
    41
    43
    41
    Treated
    40
    37
    41
    39
    Completed
    38
    37
    39
    36
    Not completed
    5
    4
    4
    5
         Consent withdrawn by subject
    1
    3
    2
    1
         Physician decision
    2
    -
    1
    1
         Death
    1
    -
    -
    -
         Lost to follow-up
    1
    1
    1
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: All enrolled subjects were not treated. Since baseline period consisted of only treated subjects, the worldwide number enrolled in the trial differs with number of subjects in baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to VP 20621 oral liquid once daily from Day 1 to 14.

    Reporting group title
    VP 20621 Low Dose and Placebo
    Reporting group description
    		 VP 20621 oral liquid containing 10^4 purified spores of non-toxigenic Clostridium difficile-strain M3 (NTCD-M3; the dormant form of a live organism) once daily from Day 1 to 7 followed by placebo matched to VP 20621 oral liquid once daily from Day 8 to 14.

    Reporting group title
    VP 20621 High Dose and Placebo
    Reporting group description
    		 VP 20621 oral liquid containing 10^7 purified spores of NTCD-M3 once daily from Day 1 to 7 followed by placebo matched to VP 20621 oral liquid once daily from Day 8 to 14.

    Reporting group title
    VP 20621 High Dose
    Reporting group description
    		 VP 20621 oral liquid containing 10^7 purified spores of NTCD-M3 once daily from Day 1 to 14.

    Reporting group values
    		 Placebo VP 20621 Low Dose and Placebo VP 20621 High Dose and Placebo VP 20621 High Dose Total
    Number of subjects
    		 43 41 43 41 168
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.7 ( 19.19 ) 58.2 ( 14.42 ) 57.2 ( 18.46 ) 60.6 ( 16.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 26 26 24 28 104
        Male
    		 17 15 19 13 64

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to VP 20621 oral liquid once daily from Day 1 to 14.

    Reporting group title
    VP 20621 Low Dose and Placebo
    Reporting group description
    		 VP 20621 oral liquid containing 10^4 purified spores of non-toxigenic Clostridium difficile-strain M3 (NTCD-M3; the dormant form of a live organism) once daily from Day 1 to 7 followed by placebo matched to VP 20621 oral liquid once daily from Day 8 to 14.

    Reporting group title
    VP 20621 High Dose and Placebo
    Reporting group description
    		 VP 20621 oral liquid containing 10^7 purified spores of NTCD-M3 once daily from Day 1 to 7 followed by placebo matched to VP 20621 oral liquid once daily from Day 8 to 14.

    Reporting group title
    VP 20621 High Dose
    Reporting group description
    		 VP 20621 oral liquid containing 10^7 purified spores of NTCD-M3 once daily from Day 1 to 14.

    Subject analysis set title
    Intent-to-Treat-Safety (ITT-S) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT-S population was defined as all randomized subjects who received at least 1 dose of study drug.

    Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [1]
    End point description
    An adverse event (AE) is any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiological observations occurring in a study subject, regardless of causal relationship. TEAEs were defined as all AEs that start during the study drug treatment period (and up to 7 days after the last dose of the study drug) and were not seen at baseline, or were seen at baseline but increased in frequency and/or severity during the study drug treatment period (and up to 7 days after the last dose of study drug). SAE was any AE that results in any of the following outcomes: death, a life-threatening event, inpatient hospitalization or prolongation of an existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, other medically important events based upon approrpriate medical judgement.
    End point type
    Primary
    End point timeframe
    Baseline up to 7 days after the last dose of study drug (up to Week 3)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not planned for this endpoint.
    End point values
    		 Placebo VP 20621 Low Dose and Placebo VP 20621 High Dose and Placebo VP 20621 High Dose
    Number of subjects analysed
    43 [2]
    41 [3]
    43 [4]
    41 [5]
    Units: subjects
        Subjects with TEAEs
    37
    33
    34
    31
        Subjects with treatment-emergent SAEs
    3
    1
    1
    2
    Notes
    [2] - ITT-S population.
    [3] - ITT-S population.
    [4] - ITT-S population.
    [5] - ITT-S population.
    No statistical analyses for this end point

    Primary: Number of Subjects With Positive Clostridium Difficile Stool Cultures Demonstrating Non-Toxigenic Clostridium Difficile-Strain M3

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    End point title
    		 Number of Subjects With Positive Clostridium Difficile Stool Cultures Demonstrating Non-Toxigenic Clostridium Difficile-Strain M3
    End point description
    End point type
    Primary
    End point timeframe
    After study drug administration period (14 days) through Week 6
    End point values
    		 Placebo VP 20621 Low Dose and Placebo VP 20621 High Dose and Placebo VP 20621 High Dose
    Number of subjects analysed
    43 [6]
    41 [7]
    43 [8]
    41 [9]
    Units: subjects
    4
    26
    31
    29
    Notes
    [6] - ITT-S population.
    [7] - ITT-S population.
    [8] - ITT-S population.
    [9] - ITT-S population.
    Statistical analysis title
    		 Low dose+placebo versus placebo
    Statistical analysis description
    Treatment comparison with placebo using two-sided Chi-Square test at significance level p=0.05.
    Comparison groups
    VP 20621 Low Dose and Placebo v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.0001
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 High dose+placebo versus placebo
    Statistical analysis description
    Treatment comparison with placebo using two-sided Chi-Square test at significance level p=0.05.
    Comparison groups
    Placebo v VP 20621 High Dose and Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 High dose versus placebo
    Statistical analysis description
    Treatment comparison with placebo using two-sided Chi-Square test at significance level p=0.05.
    Comparison groups
    VP 20621 High Dose v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Number of Subjects With CDI Recurrence

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    End point title
    		 Number of Subjects With CDI Recurrence
    End point description
    CDI recurrence was defined as at least 1 event characterized by ALL of the following: >=3 unformed (loose or watery) stools within 24 hours (data derived from Diarrhea case report form (CRF) page which was to be completed for any clinical event of diarrhea or loose/watery stool occurring between Day 1 and Week 6); a positive C. difficile stool assay, or pseudomembranes on endoscopy/surgery; and no other likely cause of the diarrhea in the opinion of the investigator.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) up to Week 6
    End point values
    		 Placebo VP 20621 Low Dose and Placebo VP 20621 High Dose and Placebo VP 20621 High Dose
    Number of subjects analysed
    43 [10]
    41 [11]
    43 [12]
    41 [13]
    Units: subjects
    13
    6
    2
    6
    Notes
    [10] - ITT-S population.
    [11] - ITT-S population.
    [12] - ITT-S population.
    [13] - ITT-S population.
    Statistical analysis title
    		 Low dose+placebo versus placebo
    Statistical analysis description
    Treatment comparison with placebo using two-sided Chi-Square test at significance level p=0.05.
    Comparison groups
    VP 20621 Low Dose and Placebo v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.088
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 High dose+placebo versus placebo
    Statistical analysis description
    Treatment comparison with placebo using two-sided Chi-Square test at significance level p=0.05.
    Comparison groups
    VP 20621 High Dose and Placebo v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 High dose versus placebo
    Statistical analysis description
    Treatment comparison with placebo using two-sided Chi-Square test at significance level p=0.05.
    Comparison groups
    VP 20621 High Dose v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.088
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Number of Subjects With Use of Antibacterial Treatment for CDI

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    End point title
    		 Number of Subjects With Use of Antibacterial Treatment for CDI
    End point description
    Any antibacterial medication used after Day 1 for which the investigator selected the indication “antibacterial for C. difficile infection”.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) up to Week 6
    End point values
    		 Placebo VP 20621 Low Dose and Placebo VP 20621 High Dose and Placebo VP 20621 High Dose
    Number of subjects analysed
    43 [14]
    41 [15]
    43 [16]
    41 [17]
    Units: subjects
    14
    6
    4
    7
    Notes
    [14] - ITT-S population.
    [15] - ITT-S population.
    [16] - ITT-S population.
    [17] - ITT-S population.
    Statistical analysis title
    		 Low dose+placebo versus placebo
    Statistical analysis description
    Treatment comparison with placebo using two-sided Chi-Square test at significance level p=0.05.
    Comparison groups
    VP 20621 Low Dose and Placebo v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.054
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 High dose+placebo versus placebo
    Statistical analysis description
    Treatment comparison with placebo using two-sided Chi-Square test at significance level p=0.05.
    Comparison groups
    VP 20621 High Dose and Placebo v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 High dose versus placebo
    Statistical analysis description
    Treatment comparison with placebo using two-sided Chi-Square test at significance level p=0.05.
    Comparison groups
    VP 20621 High Dose v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.101
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Number of Subjects With Clinical Events of Diarrhea or Loose/Watery Stools

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    End point title
    		 Number of Subjects With Clinical Events of Diarrhea or Loose/Watery Stools
    End point description
    Data were derived from all AEs starting on or after Day 1 for which a Diarrhea CRF page was completed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) up to Week 6
    End point values
    		 Placebo VP 20621 Low Dose and Placebo VP 20621 High Dose and Placebo VP 20621 High Dose
    Number of subjects analysed
    43 [18]
    41 [19]
    43 [20]
    41 [21]
    Units: subjects
    33
    23
    25
    23
    Notes
    [18] - ITT-S population.
    [19] - ITT-S population.
    [20] - ITT-S population.
    [21] - ITT-S population.
    Statistical analysis title
    		 Low dose+placebo versus placebo
    Statistical analysis description
    Treatment comparison with placebo using two-sided Chi-Square test at significance level p=0.05.
    Comparison groups
    Placebo v VP 20621 Low Dose and Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.045
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 High dose+placebo versus placebo
    Statistical analysis description
    Treatment comparison with placebo using two-sided Chi-Square test at significance level p=0.05.
    Comparison groups
    VP 20621 High Dose and Placebo v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.066
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 High dose versus placebo
    Statistical analysis description
    Treatment comparison with placebo using two-sided Chi-Square test at significance level p=0.05.
    Comparison groups
    VP 20621 High Dose v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.045
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Time to First CDI Recurrence

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    End point title
    		 Time to First CDI Recurrence
    End point description
    CDI recurrence was defined as at least 1 event characterized by ALL of the following: >=3 unformed (loose or watery) stools within 24 hours (data derived from Diarrhea CRF page which was to be completed for any clinical event of diarrhea or loose/watery stool occurring between Day 1 and Week 6); a positive C. difficile stool assay, or pseudomembranes on endoscopy/surgery; and no other likely cause of the diarrhea in the opinion of the investigator. Time of onset is from date of randomization to date of first CDI recurrence. Time to first CDI recurrence was assessed using Kaplan-Meier curve. '99999' in the below reported data indicates that median time to event was not evaluable due to small number of subjects (<50%) with CDI recurrence.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) up to Week 6
    End point values
    		 Placebo VP 20621 Low Dose and Placebo VP 20621 High Dose and Placebo VP 20621 High Dose
    Number of subjects analysed
    43 [22]
    41 [23]
    43 [24]
    41 [25]
    Units: days
        median (full range (min-max))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [22] - ITT-S population.
    [23] - ITT-S population.
    [24] - ITT-S population.
    [25] - ITT-S population.
    Statistical analysis title
    		 Low dose+placebo versus placebo
    Comparison groups
    Placebo v VP 20621 Low Dose and Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.109
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 High dose+placebo versus placebo
    Comparison groups
    VP 20621 High Dose and Placebo v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 High dose versus placebo
    Comparison groups
    VP 20621 High Dose v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.094
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 26
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to VP 20621 oral liquid once daily from Day 1 to 14.

    Reporting group title
    VP20621 Low Dose and Placebo
    Reporting group description
    		 VP 20621 oral liquid containing 10^4 purified spores of NTCD-M3 once daily from Day 1 to 7 followed by placebo matched to VP 20621 oral liquid once daily from Day 8 to 14.

    Reporting group title
    VP20621 High Dose and Placebo
    Reporting group description
    		 VP 20621 oral liquid containing 10^7 purified spores of NTCD-M3 once daily from Day 1 to 7 followed by placebo matched to VP 20621 oral liquid once daily from Day 8 to 14.

    Reporting group title
    VP20621 High Dose
    Reporting group description
    		 VP 20621 oral liquid containing 10^7 purified spores of NTCD-M3 once daily from Day 1 to 14.

    Serious adverse events
    		 Placebo VP20621 Low Dose and Placebo VP20621 High Dose and Placebo VP20621 High Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 43 (18.60%)
    5 / 41 (12.20%)
    8 / 43 (18.60%)
    6 / 41 (14.63%)
         number of deaths (all causes)
    1
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cerebrovascular arteriovenous malformation
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Knee arthroplasty
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac chest pain
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 41 (4.88%)
    3 / 43 (6.98%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dependence
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    2 / 43 (4.65%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    2 / 43 (4.65%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo VP20621 Low Dose and Placebo VP20621 High Dose and Placebo VP20621 High Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 43 (86.05%)
    31 / 41 (75.61%)
    34 / 43 (79.07%)
    34 / 41 (82.93%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 43 (4.65%)
    6 / 41 (14.63%)
    4 / 43 (9.30%)
    3 / 41 (7.32%)
         occurrences all number
    3
    11
    6
    3
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 41 (2.44%)
    2 / 43 (4.65%)
    3 / 41 (7.32%)
         occurrences all number
    2
    1
    2
    6
    Abdominal pain
         subjects affected / exposed
    16 / 43 (37.21%)
    6 / 41 (14.63%)
    9 / 43 (20.93%)
    9 / 41 (21.95%)
         occurrences all number
    25
    14
    11
    15
    Abdominal pain upper
         subjects affected / exposed
    1 / 43 (2.33%)
    5 / 41 (12.20%)
    2 / 43 (4.65%)
    3 / 41 (7.32%)
         occurrences all number
    1
    5
    2
    5
    Constipation
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 41 (4.88%)
    2 / 43 (4.65%)
    4 / 41 (9.76%)
         occurrences all number
    1
    2
    2
    4
    Diarrhoea
         subjects affected / exposed
    30 / 43 (69.77%)
    21 / 41 (51.22%)
    27 / 43 (62.79%)
    24 / 41 (58.54%)
         occurrences all number
    117
    69
    84
    82
    Dyspepsia
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 41 (2.44%)
    2 / 43 (4.65%)
    5 / 41 (12.20%)
         occurrences all number
    4
    1
    3
    7
    Flatulence
         subjects affected / exposed
    7 / 43 (16.28%)
    9 / 41 (21.95%)
    10 / 43 (23.26%)
    6 / 41 (14.63%)
         occurrences all number
    7
    11
    10
    9
    Nausea
         subjects affected / exposed
    4 / 43 (9.30%)
    5 / 41 (12.20%)
    4 / 43 (9.30%)
    2 / 41 (4.88%)
         occurrences all number
    9
    7
    5
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 43 (4.65%)
    3 / 41 (7.32%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
         occurrences all number
    2
    3
    1
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    3 / 41 (7.32%)
         occurrences all number
    1
    0
    1
    3
    Infections and infestations
    Clostridial infection
         subjects affected / exposed
    9 / 43 (20.93%)
    2 / 41 (4.88%)
    2 / 43 (4.65%)
    4 / 41 (9.76%)
         occurrences all number
    13
    2
    3
    4
    Nasopharyngitis
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    3 / 41 (7.32%)
         occurrences all number
    4
    1
    2
    3
    Urinary tract infection
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    6 / 41 (14.63%)
         occurrences all number
    3
    1
    1
    7

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Mar 2011
    1. The duration of the study was extended from 6 weeks to 6 months (Week 26) 2. The removal of a separate follow-up study (Protocol 20621-900) for subjects who remained positive for C. difficile at Week 6 3. Duration of treatment for metronidazole or oral vancomycin for qualifying episode of CDI was extended from a maximum of 14 days to a maximum of 21 days 4. Excluded subjects with acute febrile illness on Day 1 prior to the first dose, subjects with known immunodeficiency disorders and outpatient subjects with household contacts <2 years of age or who have an immunodeficiency disorder 5. The first dose of study drug was to be administered under supervision of study personnel, and subjects were to remain at the study center for at least 30 minutes after the first dose 6. The following information was to be recorded in the subject study diary: date and time of each study drug administration through Day 14, daily oral temperature measurement through Week 3; all AEs through Week 6, including severity assessment and any occurrence of specified gastrointestinal related events; date and time of any unformed (loose or watery) stools through Week 6; and medications through Week 6 7. The addition of oral temperature measurements, to be recorded at screening, Day 1, and each day through Week 3 8. A rapid urine pregnancy test performed at the study site on Day 1 prior to study drug was added for women of child-bearing potential 9. All C. difficile isolates were to be tested for toxin A/B at a central lab, and any toxin-negative C. difficile was to be further genotyped 10. All medications used within 1 week prior to study drug start and through Week 6 were to be recorded 11. Permanent discontinuation of study drug if subject had Grade 3 or 4 neutropenia during the study drug administration period 12. Clarified definitions and timeframe for several safety and efficacy endpoints, additional details to sample size assumptions, and added a Per Protocol population
    29 Mar 2011
    1. Exclusion Criteria: “non-laparoscopic” gastrointestinal surgery and specification of Cluster of Differentiation 4 count, were removed 2. New onset of medical conditions or changes in chronic disease was added to data to be recorded during follow-up Weeks 10-26 3. Megacolon was removed as a complication to be recorded for the qualifying episode of CDI
    06 Jan 2012
    1. Inclusion Criteria: the time frame for the start of symptoms of the qualifying episode of CDI was changed from 21 days to 28 days, relative to randomization 2. Clarified the required procedures if screening and randomization occurred on the same day 3. A total of up to approximately 70 sites was increased from previously allowed 50 study sites 4. Surgery removed as source for documentation of colonic pseudomembranes in inclusion criteria 5. Excluded subjects with a known hypersensitivity to any ingredient in the study formulation 6. Toxin A was removed from the testing of C. difficile isolates at the central lab since Toxin B is far more common 7. The time period of events occurring between Day 1 and Week 6 was added, with regard to completion of the separate Diarrhea CRF page 8. Temperature excursions between -20 to 25 degree Celsius were permitted for up to 72 hours 9. The subgroup of gender was added

    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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