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    Clinical Trial Results:
    A Phase II randomized, placebo-controlled, double-blind, dose ranging study of a Clostridium difficile toxoid vaccine (ACAM-CDIFF) in subjects with Clostridium difficile-associated infection(CDI)

    Summary
    EudraCT number
    2008-004907-69
    Trial protocol
    GB  
    Global end of trial date
    11 Jul 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Feb 2016
    First version publication date
    22 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    H-030-011
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00772343
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur Inc
    Sponsor organisation address
    1 Discovery Drive, Swiftwater, United States, 18370
    Public contact
    Director, Clinical Development, Sanofi Pasteur Inc, 1 570-957-0746, guy.debruyn@sanofipasteur.com
    Scientific contact
    Director, Clinical Development, Sanofi Pasteur Inc, 1 570-957-0746, guy.debruyn@sanofipasteur.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
    05 Dec 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jul 2011
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the event rate of CDI in groups assigned to ACAM-CDIFF vaccine (pooled groups) versus placebo in the 9 week period after the third dose of study vaccine (Study Days 29 to 91) in subjects with primary CDI up to 12 days prior to the first dose of study vaccine, receiving antibiotic standard of care. Primary CDI is defined as a documented, laboratory-confirmed CDI event that is either the first in the subject’s history or is occurring more than 90 days after a prior event. This study was halted due to operational futility before the planned number of subjects was enrolled. The actual number of subjects enrolled (116) was far below what was originally planned (612). A formal analysis of event rates could not be performed and the analyses are displayed descriptively. The summary and analysis were performed on the per-protocol analysis set and the intent-to-treat analysis set.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were randomized and vaccinated in the study. Vaccinations were performed by qualified and trained study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After vaccination, subjects were also kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment was also available on site in case of any immediate allergic reactions.
    Background therapy
    During the screening period, subjects were to be treated according to recommended clinical guidelines, which could include metronidazole or vancomycin.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    11 May 2009
    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 Kingdom: 39
    Country: Number of subjects enrolled
    United States: 77
    Worldwide total number of subjects
    116
    EEA total number of subjects
    39
    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)
    64
    From 65 to 84 years
    40
    85 years and over
    12

    Subject disposition

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    Recruitment
    Recruitment details
    Study subjects were enrolled from 11 May 2009 to 18 November 2010 at 11 clinical centers in the United Kingdom and from 22 December 2009 to 11 July 2011 at 26 clinical centers in the United States.

    Pre-assignment
    Screening details
    A total of 116 subjects who met all inclusion criteria and none of the exclusion criteria were enrolled; 113 subjects were vaccinated.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Assessor
    Blinding implementation details
    All subjects and all study site personnel, with the exception of the pharmacist(s) (or designee) who prepared the study vaccine for administration, were blinded to the treatment schedule. The pharmacist (or designee) was not to inform any of the investigational staff of the treatment assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    50 µg + AlOH
    Arm description
    Subjects who received 3 injections of 50 µg ACAM-CDIFF vaccine plus aluminum hydroxide (AlOH) adjuvant administered on Days 0, 7, and 28.
    Arm type
    Experimental

    Investigational medicinal product name
    ACAM-CDIFF™ Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL dose, intramuscular, 3 injections administered on Days 0, 7, and 28.

    Arm title
    100 µg
    Arm description
    Subjects who received 3 injections of 100 µg ACAM-CDIFF Vaccine (no adjuvant) administered on Days 0, 7, and 28.
    Arm type
    Experimental

    Investigational medicinal product name
    ACAM-CDIFF™ Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL dose, intramuscular, 3 injections administered on Days 0, 7, and 28.

    Arm title
    100 µg + AlOH
    Arm description
    Subjects who received 3 injections of 100 µg ACAM-CDIFF Vaccine plus AlOH adjuvant administered on Days 0, 7, and 28.
    Arm type
    Experimental

    Investigational medicinal product name
    ACAM-CDIFF™ Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL dose, intramuscular, 3 injections administered on Days 0, 7, and 28.

    Arm title
    Placebo
    Arm description
    Subjects who received 3 injections of placebo vaccine (0.9% normal saline) administered on Days 0, 7, and 28.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL dose, intramuscular, 3 injections administered on Days 0, 7, and 28.

    Number of subjects in period 1 [1]
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Started
    17
    18
    40
    38
    Completed
    11
    16
    35
    33
    Not completed
    6
    2
    5
    5
         Protocol deviation
    -
    -
    3
    -
         Death
    2
    1
    -
    1
         Intolerable adverse event
    1
    -
    -
    -
         Administrative decision
    -
    -
    -
    1
         Not specified
    1
    -
    -
    -
         Consent withdrawn by subject
    1
    1
    1
    3
         Lost to follow-up
    1
    -
    1
    -
    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: A total of 116 subjects were enrolled in the study; however, only 113 subjects were vaccinated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    50 µg + AlOH
    Reporting group description
    Subjects who received 3 injections of 50 µg ACAM-CDIFF vaccine plus aluminum hydroxide (AlOH) adjuvant administered on Days 0, 7, and 28.

    Reporting group title
    100 µg
    Reporting group description
    Subjects who received 3 injections of 100 µg ACAM-CDIFF Vaccine (no adjuvant) administered on Days 0, 7, and 28.

    Reporting group title
    100 µg + AlOH
    Reporting group description
    Subjects who received 3 injections of 100 µg ACAM-CDIFF Vaccine plus AlOH adjuvant administered on Days 0, 7, and 28.

    Reporting group title
    Placebo
    Reporting group description
    Subjects who received 3 injections of placebo vaccine (0.9% normal saline) administered on Days 0, 7, and 28.

    Reporting group values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo Total
    Number of subjects
    17 18 40 38 113
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    8 10 24 21 63
        From 65-84 years
    7 7 14 10 38
        85 years and over
    2 1 2 7 12
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    62.1 ± 21.4 61.7 ± 15.6 59.5 ± 18.6 65.6 ± 17.3 -
    Gender categorical
    Units: Subjects
        Female
    12 13 28 24 77
        Male
    5 5 12 14 36

    End points

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    End points reporting groups
    Reporting group title
    50 µg + AlOH
    Reporting group description
    Subjects who received 3 injections of 50 µg ACAM-CDIFF vaccine plus aluminum hydroxide (AlOH) adjuvant administered on Days 0, 7, and 28.

    Reporting group title
    100 µg
    Reporting group description
    Subjects who received 3 injections of 100 µg ACAM-CDIFF Vaccine (no adjuvant) administered on Days 0, 7, and 28.

    Reporting group title
    100 µg + AlOH
    Reporting group description
    Subjects who received 3 injections of 100 µg ACAM-CDIFF Vaccine plus AlOH adjuvant administered on Days 0, 7, and 28.

    Reporting group title
    Placebo
    Reporting group description
    Subjects who received 3 injections of placebo vaccine (0.9% normal saline) administered on Days 0, 7, and 28.

    Primary: Number of Cases of Clostridium difficile Infection (CDI) Recurrence After A Third dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or a Placebo in Subjects with CDI

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    End point title
    Number of Cases of Clostridium difficile Infection (CDI) Recurrence After A Third dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or a Placebo in Subjects with CDI [1]
    End point description
    A clostridium difficile infection (CDI) recurrence event must have satisfied the conditions of a CDI event and if the patient was on a recommended course of antibiotics, must have completed this and have been off these antibiotics for a minimum of 48 hours and must have had a minimum of 2 consecutive days without any diarrhea. Analysis was in the Per-protocol analysis set for efficacy. A CDI event was defined as: (i) passage of 3 or more loose stools within a 24 hour period (that conform to the shape of the container it is placed into), and (ii) a positive result of stool toxin testing using either ELISA/EIA or PCR, and (iii) absence of another identified cause for diarrhoea. In addition, a stool cytotoxicity assay was required to confirm positive ELISA results.
    End point type
    Primary
    End point timeframe
    9-week period after the third dose of study vaccine. Days 29 to 91. Additional timepoints beyond Day 91 were collected and examined in other analyses.
    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: The study was terminated early, therefore only descriptive analyses were performed. The original planned comparisons were not performed.
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    6
    9
    10
    20
    Units: Number of cases
    number (not applicable)
        UK; -12 to 28
    0
    1
    0
    0
        UK; 29 to 91
    0
    0
    0
    0
        UK; -12 to 91
    0
    1
    0
    0
        UK; 92 to 210
    0
    0
    0
    0
        US; -12 to 28
    1
    0
    1
    1
        US; 29 to 91
    0
    1
    0
    0
        US; -12 to 91
    1
    1
    1
    1
        US; 92 to 210
    0
    0
    0
    0
        All; -12 to 28
    1
    1
    1
    1
        All; 29 to 91
    0
    1
    0
    0
        All; -12 to 91
    1
    2
    1
    1
        All; 92 to 210
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentrations of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Subjects Aged 18 to 64 years with Clostridium difficile Infection

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    End point title
    Geometric Mean Concentrations of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Subjects Aged 18 to 64 years with Clostridium difficile Infection
    End point description
    Anti-toxin A and B IgG antibodies were detected using toxin antibody enzyme-linked immunosorbent assay (ELISA). Analysis was in the Intent-to-treat analysis set for immunogenicity.
    End point type
    Secondary
    End point timeframe
    Day 0, 7, 14, 28, 42, 91, and 210
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    6
    10
    22
    20
    Units: Concentrations (EU/mL)
    geometric mean (confidence interval 95%)
        Toxin A IgG; Day 0
    1.6 (0.64 to 4.02)
    0.81 (0.68 to 0.96)
    1.18 (0.72 to 1.91)
    0.95 (0.69 to 1.3)
        Toxin A IgG; Day 7
    5.81 (0.68 to 49.96)
    0.94 (0.67 to 1.33)
    1.82 (0.83 to 4.03)
    1.19 (0.79 to 1.79)
        Toxin A IgG; Day 14
    165.8 (11.93 to 2303.23)
    7.09 (1.84 to 27.35)
    8.62 (3.45 to 21.55)
    1.27 (0.8 to 2.04)
        Toxin A IgG; Day 28
    190.8 (21.53 to 1690.7)
    15.07 (3.23 to 70.25)
    14.72 (5.97 to 36.28)
    1.49 (0.74 to 3)
        Toxin A IgG; Day 42
    229.22 (47.77 to 1099.99)
    40.32 (13.13 to 123.79)
    104.93 (43.65 to 252.28)
    1.1 (0.72 to 1.68)
        Toxin A IgG; Day 91
    98.64 (14.52 to 670.26)
    25.11 (8.43 to 74.81)
    36.13 (16.51 to 79.07)
    1.58 (0.76 to 3.25)
        Toxin A IgG; Day 210
    25.53 (3.62 to 180.22)
    8.76 (3.39 to 22.67)
    13.14 (5.31 to 32.52)
    1.4 (0.71 to 2.76)
        Toxin B IgG; Day 0
    4.12 (0.58 to 29.19)
    0.72 (0.36 to 1.46)
    1.84 (0.73 to 4.64)
    1.66 (0.5 to 5.49)
        Toxin B IgG; Day 7
    5.88 (0.6 to 57.97)
    0.76 (0.41 to 1.41)
    5.22 (1.5 to 18.13)
    2.32 (0.57 to 9.49)
        Toxin B IgG; Day 14
    52.4 (2.69 to 1018.7)
    3.94 (0.43 to 36.03)
    19.61 (4.64 to 82.92)
    2.89 (0.63 to 13.22)
        Toxin B IgG; Day 28
    61.47 (3.88 to 974.48)
    12.58 (2.21 to 71.46)
    35.58 (11.58 to 109.31)
    4.53 (0.99 to 20.8)
        Toxin B IgG; Day 42
    162.76 (31.41 to 843.4)
    83.97 (26.15 to 269.59)
    110.35 (46.24 to 263.36)
    3.75 (0.81 to 17.32)
        Toxin B IgG; Day 91
    117.64 (37.08 to 373.21)
    35.74 (10.39 to 123)
    42.98 (17.39 to 106.21)
    4.43 (1.1 to 17.9)
        Toxin B IgG; Day 210
    44.71 (8.21 to 243.47)
    9.82 (1.93 to 50.02)
    22.26 (8.33 to 59.51)
    2.68 (0.75 to 9.52)
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentrations of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Subjects Aged 65 Years and Older with Clostridium difficile Infection

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    End point title
    Geometric Mean Concentrations of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Subjects Aged 65 Years and Older with Clostridium difficile Infection
    End point description
    Anti-toxin A and B IgG antibodies were detected using toxin antibody enzyme-linked immunosorbent assay (ELISA). Analysis was in the Intent-to-treat analysis set for immunogenicity.
    End point type
    Secondary
    End point timeframe
    Day 0, 7, 14, 28, 42, 91, and 210
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    8
    7
    15
    14
    Units: Concentrations (EU/mL)
    geometric mean (confidence interval 95%)
        Toxin A IgG; Day 0
    0.75 (0.75 to 0.75)
    0.75 (0.75 to 0.75)
    0.75 (0.75 to 0.75)
    1.11 (0.69 to 1.81)
        Toxin A IgG; Day 7
    0.75 (0.75 to 0.75)
    0.91 (0.57 to 1.43)
    0.81 (0.68 to 0.98)
    1.48 (0.8 to 2.74)
        Toxin A IgG; Day 14
    2.43 (0.4 to 14.87)
    10.86 (0.37 to 315.32)
    2.23 (0.71 to 7.02)
    1.53 (0.73 to 3.19)
        Toxin A IgG; Day 28
    7.28 (0.37 to 142.43)
    18.84 (1.11 to 318.57)
    6.25 (2.29 to 17.1)
    1.49 (0.68 to 3.28)
        Toxin A IgG; Day 42
    31.61 (4.07 to 245.67)
    170.61 (17.97 to 1619.81)
    66.06 (28.72 to 151.96)
    1.08 (0.55 to 2.15)
        Toxin A IgG; Day 91
    14 (1.87 to 104.85)
    59.41 (7.89 to 447.4)
    24.16 (10.56 to 55.27)
    1.25 (0.65 to 2.38)
        Toxin A IgG; Day 210
    7.38 (0.88 to 61.54)
    9.63 (1.05 to 88.11)
    7.88 (3.15 to 19.72)
    1.56 (0.73 to 3.32)
        Toxin B IgG; Day 0
    1.07 (0.1 to 11.06)
    0.61 (0.31 to 1.2)
    1.18 (0.54 to 2.58)
    0.69 (0.28 to 1.68)
        Toxin B IgG; Day 7
    1.51 (0.13 to 17.68)
    1.38 (0.24 to 8.02)
    1.6 (0.65 to 3.93)
    1.15 (0.37 to 3.55)
        Toxin B IgG; Day 14
    2.74 (0.14 to 54.12)
    29.25 (0.73 to 1169.7)
    5.63 (0.92 to 34.35)
    1.28 (0.42 to 3.87)
        Toxin B IgG; Day 28
    4.07 (0.13 to 123.35)
    116.3 (9.49 to 1424.82)
    13.64 (3.24 to 57.48)
    2.68 (0.68 to 10.62)
        Toxin B IgG; Day 42
    9.21 (0.52 to 163.49)
    666.15 (140.53 to 3157.81)
    56.76 (16.61 to 193.93)
    2.57 (0.7 to 9.34)
        Toxin B IgG; Day 91
    5.28 (0.26 to 105.48)
    177.31 (18.87 to 1666.38)
    36.2 (12.04 to 108.84)
    2.86 (0.71 to 11.57)
        Toxin B IgG; Day 210
    2.98 (0.21 to 42.34)
    28.39 (3.39 to 237.67)
    14.11 (4.3 to 46.35)
    3.44 (0.86 to 13.7)
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentrations of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Seropositive Subjects with Clostridium difficile Infection

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    End point title
    Geometric Mean Concentrations of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Seropositive Subjects with Clostridium difficile Infection
    End point description
    Anti-toxin A and B IgG antibodies were detected using toxin antibody enzyme-linked immunosorbent assay (ELISA). Analysis was in the Intent-to-treat analysis set for immunogenicity.
    End point type
    Secondary
    End point timeframe
    Day 0, 7, 14, 28, 42, 91, and 210
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    14
    17
    37
    34
    Units: Concentrations (EU/mL)
    geometric mean (confidence interval 95%)
        Toxin A IgG; Day 0
    3.41 (1.08 to 10.74)
    1.6 (1.6 to 1.6)
    8.87 (1.15 to 68.59)
    3.87 (1.64 to 9.12)
        Toxin A IgG; Day 7
    23.32 (0.24 to 2297.32)
    2.3 (2.3 to 2.3)
    51.52 (7.97 to 332.91)
    6.47 (3.25 to 12.86)
        Toxin A IgG; Day 14
    525.66 (23.3 to 11857.26)
    10.2 (10.2 to 10.2)
    203.72 (18.19 to 2281.77)
    7.62 (2.94 to 19.75)
        Toxin A IgG; Day 28
    602.18 (39.21 to 9248.47)
    15.3 (15.3 to 15.3)
    183.01 (26.26 to 1275.53)
    8.88 (2.12 to 37.26)
        Toxin A IgG; Day 42
    510.19 (38.17 to 6820.17)
    48 (48 to 48)
    247.09 (63.87 to 955.99)
    8.34 (1.95 to 35.76)
        Toxin A IgG; Day 91
    147.29 (6.86 to 3163.8)
    29.6 (29.6 to 29.6)
    75.43 (12.71 to 447.79)
    4.49 (1 to 20.17)
        Toxin A IgG; Day 210
    66.04 (21.25 to 205.19)
    15.3 (15.3 to 15.3)
    44.06 (12.17 to 159.52)
    2.14 (0.59 to 7.85)
        Toxin B IgG; Day 0
    31.82 (2.54 to 397.99)
    2.35 (1.31 to 4.24)
    8.35 (3.68 to 18.97)
    20.64 (2.77 to 153.99)
        Toxin B IgG; Day 7
    53.45 (4.11 to 695.1)
    5.18 (0.92 to 29.13)
    24.23 (9.4 to 62.47)
    36.63 (3.06 to 437.96)
        Toxin B IgG; Day 14
    419.77 (88.9 to 1982.06)
    490.33 (29.49 to 8153.86)
    195.74 (66.48 to 576.3)
    45.2 (3.85 to 530.79)
        Toxin B IgG; Day 28
    323.97 (123.46 to 850.11)
    416.17 (28.89 to 5994.87)
    177.96 (72.59 to 436.25)
    34.61 (3.16 to 378.5)
        Toxin B IgG; Day 42
    352.72 (105.35 to 1180.89)
    400.86 (34.57 to 4647.68)
    230.69 (89.29 to 595.97)
    35.39 (3.46 to 361.65)
        Toxin B IgG; Day 91
    144.87 (29.43 to 713.12)
    270.84 (14.71 to 4987.99)
    112.17 (48.8 to 257.81)
    29.96 (3.5 to 256.11)
        Toxin B IgG; Day 210
    87.94 (16.51 to 468.43)
    83.61 (7.58 to 922.53)
    79.46 (34.56 to 182.67)
    5.72 (0.69 to 47.46)
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentrations of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Seronegative Subjects with Clostridium difficile Infection

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    End point title
    Geometric Mean Concentrations of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Seronegative Subjects with Clostridium difficile Infection
    End point description
    Anti-toxin A and B IgG antibodies were detected using toxin antibody enzyme-linked immunosorbent assay (ELISA). Analysis was in the Intent-to-treat analysis set for immunogenicity.
    End point type
    Secondary
    End point timeframe
    Day 0, 7, 14, 28, 42, 91, and 210
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    14
    17
    37
    34
    Units: Concentrations (EU/mL)
    geometric mean (confidence interval 95%)
        Toxin A IgG; Day 0
    0.75 (0.75 to 0.75)
    0.75 (0.75 to 0.75)
    0.75 (0.75 to 0.75)
    0.75 (0.75 to 0.75)
        Toxin A IgG; Day 7
    0.9 (0.6 to 1.34)
    0.88 (0.7 to 1.1)
    0.82 (0.74 to 0.92)
    0.86 (0.73 to 1)
        Toxin A IgG; Day 14
    6.11 (0.92 to 40.56)
    8.21 (2.11 to 31.91)
    3.22 (1.75 to 5.91)
    0.85 (0.7 to 1.03)
        Toxin A IgG; Day 28
    14.74 (1.78 to 121.79)
    16.46 (4.45 to 60.92)
    7.54 (3.97 to 14.29)
    1.05 (0.66 to 1.66)
        Toxin A IgG; Day 42
    45.06 (10.45 to 194.3)
    66.66 (23.58 to 188.43)
    84.39 (43.82 to 162.52)
    0.79 (0.73 to 0.86)
        Toxin A IgG; Day 91
    20.64 (4.17 to 102.1)
    35.05 (13.4 to 91.7)
    29.18 (15.96 to 53.34)
    1.16 (0.7 to 1.91)
        Toxin A IgG; Day 210
    9.04 (2.14 to 38.11)
    8.77 (3.43 to 22.37)
    9.56 (4.77 to 19.14)
    1.3 (0.73 to 2.3)
        Toxin B IgG; Day 0
    0.4 (0.4 to 0.4)
    0.4 (0.4 to 0.4)
    0.4 (0.4 to 0.4)
    0.4 (0.4 to 0.4)
        Toxin B IgG; Day 7
    0.51 (0.29 to 0.91)
    0.49 (0.36 to 0.65)
    0.6 (0.33 to 1.08)
    0.48 (0.39 to 0.59)
        Toxin B IgG; Day 14
    1.08 (0.32 to 3.65)
    1.31 (0.48 to 3.55)
    1.3 (0.5 to 3.35)
    0.52 (0.4 to 0.69)
        Toxin B IgG; Day 28
    1.83 (0.24 to 14)
    8.62 (2.69 to 27.62)
    4.71 (1.84 to 12.08)
    1.28 (0.51 to 3.26)
        Toxin B IgG; Day 42
    8.13 (0.88 to 75.06)
    108.24 (34.31 to 341.51)
    41.35 (16.14 to 105.95)
    1.15 (0.52 to 2.55)
        Toxin B IgG; Day 91
    4.6 (0.3 to 70.42)
    34.1 (12.45 to 93.4)
    18.65 (7.34 to 47.38)
    1.6 (0.64 to 3.97)
        Toxin B IgG; Day 210
    2.98 (0.42 to 21.17)
    6.36 (2.01 to 20.15)
    6.67 (2.74 to 16.25)
    2.03 (0.7 to 5.84)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Clostridium difficile Infection (CDI) Achieving Seroconversion After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo

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    End point title
    Percentage of Subjects with Clostridium difficile Infection (CDI) Achieving Seroconversion After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo
    End point description
    Anti-toxin A and B IgG antibodies were detected using toxin antibody enzyme-linked immunosorbent assay (ELISA). Seroconversion was defined as a minimum 2-fold and 4-fold increase in antibody levels for toxins A and B individually and the composite of A and B (a fold-rise achieved for both toxins A and B simultaneously) from baseline. Analysis was in the Intent-to-treat analysis set for immunogenicity.
    End point type
    Secondary
    End point timeframe
    Day 0, 7, 14, 28, 42, 91, and 210
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    5
    6
    7
    9
    Units: Percentage of subjects
    number (not applicable)
        Toxin A IgG; ≥2-fold rise Day 7/Day 0
    20
    0
    14.3
    11.1
        Toxin A IgG; ≥2-fold rise Day 14/Day 0
    60
    66.7
    71.4
    0
        Toxin A IgG; ≥2-fold rise Day 14/Day 7
    60
    66.7
    57.1
    0
        Toxin A IgG; ≥2-fold rise Day 28/Day 0
    60
    83.3
    71.4
    0
        Toxin A IgG; ≥2-fold rise Day 28/Day 7
    60
    83.3
    71.4
    0
        Toxin A IgG; ≥2-fold rise Day 28/Day 14
    40
    50
    28.6
    0
        Toxin A IgG; ≥2-fold rise Day 42/Day 0
    100
    100
    100
    0
        Toxin A IgG; ≥2-fold rise Day 42/Day 28
    60
    83.3
    85.7
    0
        Toxin A IgG; ≥2-fold rise Day 91/Day 0
    100
    100
    100
    0
        Toxin A IgG; ≥2-fold rise Day 210/Day 0
    80
    80
    85.7
    0
        Toxin A IgG; ≥4-fold rise Day 7/Day 0
    0
    0
    0
    0
        Toxin A IgG; ≥4-fold rise Day 14/Day 0
    60
    66.7
    71.4
    0
        Toxin A IgG; ≥4-fold rise Day 14/Day 7
    60
    66.7
    57.1
    0
        Toxin A IgG; ≥4-fold rise Day 28/Day 0
    60
    83.3
    71.4
    0
        Toxin A IgG; ≥4-fold rise Day 28/Day 7
    60
    83.3
    57.1
    0
        Toxin A IgG; ≥4-fold rise Day 28/Day 14
    40
    33.3
    28.6
    0
        Toxin A IgG; ≥4-fold rise Day 42/Day 0
    100
    83.3
    100
    0
        Toxin A IgG; ≥4-fold rise Day 42/Day 28
    40
    66.7
    42.9
    0
        Toxin A IgG; ≥4-fold rise Day 91/Day 0
    80
    100
    100
    0
        Toxin A IgG; ≥4-fold rise Day 210/Day 0
    80
    60
    85.7
    0
        Toxin B IgG; ≥2-fold rise Day 7/Day 0
    20
    16.7
    28.6
    22.2
        Toxin B IgG; ≥2-fold rise Day 14/Day 0
    60
    33.3
    71.4
    22.2
        Toxin B IgG; ≥2-fold rise Day 14/Day 7
    40
    33.3
    42.9
    0
        Toxin B IgG; ≥2-fold rise Day 28/Day 0
    40
    83.3
    85.7
    33.3
        Toxin B IgG; ≥2-fold rise Day 28/Day 7
    40
    83.3
    71.4
    33.3
        Toxin B IgG; ≥2-fold rise Day 28/Day 14
    20
    66.7
    28.6
    33.3
        Toxin B IgG; ≥2-fold rise Day 42/Day 0
    60
    100
    100
    33.3
        Toxin B IgG; ≥2-fold rise Day 42/Day 28
    40
    83.3
    42.9
    0
        Toxin B IgG; ≥2-fold rise Day 91/Day 0
    60
    100
    100
    22.2
        Toxin B IgG; ≥2-fold rise Day 210/Day 0
    60
    80
    85.7
    22.2
        Toxin B IgG; ≥4-fold rise Day 7/Day 0
    20
    16.7
    14.3
    0
        Toxin B IgG; ≥4-fold rise Day 14/Day 0
    40
    33.3
    42.9
    0
        Toxin B IgG; ≥4-fold rise Day 14/Day 7
    20
    33.3
    28.6
    0
        Toxin B IgG; ≥4-fold rise Day 28/Day 0
    40
    83.3
    85.7
    22.2
        Toxin B IgG; ≥4-fold rise Day 28/Day 7
    40
    83.3
    57.1
    11.1
        Toxin B IgG; ≥4-fold rise Day 28/Day 14
    20
    66.7
    28.6
    11.1
        Toxin B IgG; ≥4-fold rise Day 42/Day 0
    60
    100
    100
    33.3
        Toxin B IgG; ≥4-fold rise Day 42/Day 28
    20
    66.7
    42.9
    0
        Toxin B IgG; ≥4-fold rise Day 91/Day 0
    60
    83.3
    85.7
    11.1
        Toxin B IgG; ≥4-fold rise Day 210/Day 0
    60
    80
    71.4
    22.2
        Composite; ≥2-fold rise Day 7/Day 0
    0
    0
    14.3
    11.1
        Composite; ≥2-fold rise Day 14/Day 0
    40
    33.3
    57.1
    0
        Composite; ≥2-fold rise Day 14/Day 7
    40
    33.3
    42.9
    0
        Composite; ≥2-fold rise Day 28/Day 0
    40
    83.3
    57.1
    0
        Composite; ≥2-fold rise Day 28/Day 7
    40
    83.3
    42.9
    0
        Composite; ≥2-fold rise Day 28/Day 14
    20
    50
    14.3
    0
        Composite; ≥2-fold rise Day 42/Day 0
    60
    100
    100
    0
        Composite; ≥2-fold rise Day 42/Day 28
    20
    66.7
    28.6
    0
        Composite; ≥2-fold rise Day 91/Day 0
    60
    100
    100
    0
        Composite; ≥2-fold rise Day 210/Day 0
    60
    80
    71.4
    0
        Composite; ≥4-fold rise Day 7/Day 0
    0
    0
    0
    0
        Composite; ≥4-fold rise Day 14/Day 0
    40
    33.3
    42.9
    0
        Composite; ≥4-fold rise Day 14/Day 7
    20
    33.3
    28.6
    0
        Composite; ≥4-fold rise Day 28/Day 0
    40
    83.3
    57.1
    0
        Composite; ≥4-fold rise Day 28/Day 7
    40
    83.3
    42.9
    0
        Composite; ≥4-fold rise Day 28/Day 14
    20
    33.3
    14.3
    0
        Composite; ≥4-fold rise Day 42/Day 0
    60
    83.3
    100
    0
        Composite; ≥4-fold rise Day 42/Day 28
    0
    33.3
    28.6
    0
        Composite; ≥4-fold rise Day 91/Day 0
    60
    83.3
    85.7
    0
        Composite; ≥4-fold rise Day 210/Day 0
    60
    60
    57.1
    0
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Subjects with Clostridium difficile Infection

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    End point title
    Geometric Mean Titers of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Subjects with Clostridium difficile Infection
    End point description
    Anti-toxin A and B IgG antibodies were detected using toxin neutralization assay (TNA).
    End point type
    Secondary
    End point timeframe
    Day 0, 7, 14, 28, 42, 91, and 210
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    14
    17
    37
    34
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Toxin A IgG; Day 0
    17.1 (8.79 to 33.27)
    10.23 (7.16 to 14.62)
    14.69 (9.6 to 22.49)
    12.82 (8.71 to 18.88)
        Toxin A IgG; Day 7
    32.59 (9.48 to 112.02)
    13.99 (7.43 to 26.32)
    19 (9.9 to 36.48)
    15.8 (10.37 to 24.06)
        Toxin A IgG; Day 14
    216.92 (21.18 to 2221.38)
    61.08 (13.99 to 266.65)
    60.09 (26.16 to 138.05)
    16.07 (10.62 to 24.31)
        Toxin A IgG; Day 28
    423.14 (47.53 to 3767.45)
    68.07 (16.1 to 287.72)
    79.1 (37.33 to 167.6)
    15.91 (10.4 to 24.33)
        Toxin A IgG; Day 42
    718.52 (147.3 to 3504.82)
    417.65 (127.58 to 1367.22)
    435.3 (215.01 to 881.3)
    14.02 (9.48 to 20.72)
        Toxin A IgG; Day 91
    481.56 (68.61 to 3379.94)
    229.23 (90.78 to 578.81)
    292.04 (152.26 to 560.13)
    15.35 (9.76 to 24.15)
        Toxin A IgG; Day 210
    370.64 (85.97 to 1598)
    197.44 (82.02 to 475.28)
    300.49 (151.94 to 594.28)
    17.38 (10.35 to 29.2)
        Toxin B IgG; Day 0
    44.26 (9.61 to 203.88)
    11.26 (7.35 to 17.25)
    21.28 (11.35 to 39.9)
    16.82 (8.19 to 34.56)
        Toxin B IgG; Day 7
    56.95 (10.8 to 300.19)
    14.35 (6.98 to 29.5)
    35.13 (15.77 to 78.25)
    22.44 (9.58 to 52.53)
        Toxin B IgG; Day 14
    169.39 (14.74 to 1946.03)
    62.41 (9.72 to 400.84)
    93.69 (28.86 to 304.13)
    22.89 (9.62 to 54.47)
        Toxin B IgG; Day 28
    235.79 (16.13 to 3446.38)
    54.82 (9.26 to 324.65)
    84.95 (28.4 to 254.05)
    27.16 (10.99 to 67.07)
        Toxin B IgG; Day 42
    300.63 (31.64 to 2856.16)
    212.23 (44.07 to 1022.05)
    141.29 (50.62 to 394.31)
    20.36 (9.11 to 45.52)
        Toxin B IgG; Day 91
    237.06 (17.54 to 3204.1)
    144.13 (36.98 to 561.74)
    156.58 (63.82 to 384.18)
    20.38 (9.62 to 43.19)
        Toxin B IgG; Day 210
    187.85 (21.85 to 1615.33)
    162.81 (38.41 to 690.04)
    171.3 (69.19 to 424.12)
    30.32 (12.55 to 73.25)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Subjects Aged 18 to 64 years with Clostridium difficile Infection

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    End point title
    Geometric Mean Titers of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Subjects Aged 18 to 64 years with Clostridium difficile Infection
    End point description
    Anti-toxin A and B IgG antibodies were detected using toxin neutralization assay (TNA).
    End point type
    Secondary
    End point timeframe
    Day 0, 7, 14, 28, 42, 91, and 210
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    6
    10
    22
    20
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Toxin A; Day 0
    36.15 (8.7 to 150.16)
    12.14 (6.46 to 22.83)
    16.34 (9.01 to 29.64)
    10.92 (7.37 to 16.17)
        Toxin A; Day 7
    159.02 (11.93 to 2119.32)
    17.25 (5.89 to 50.53)
    25.28 (9.03 to 70.79)
    12.56 (7.73 to 20.42)
        Toxin A; Day 14
    2968 (54.81 to 160713.4)
    78.54 (9.97 to 618.67)
    90.24 (26.99 to 301.71)
    12.9 (7.71 to 21.57)
        Toxin A; Day 28
    1994.43 (58.42 to 68085.42)
    114.21 (15.69 to 831.28)
    108 (37.07 to 314.65)
    13.69 (7.85 to 23.87)
        Toxin A; Day 42
    2903.43 (283.83 to 29700.12)
    403.92 (76.98 to 2119.52)
    545.33 (227.54 to 1306.93)
    12.53 (7.61 to 20.61)
        Toxin A; Day 91
    2586.57 (58.47 to 114432.6)
    255.74 (65.21 to 1003.03)
    350.25 (153.83 to 797.45)
    15.18 (7.88 to 29.24)
        Toxin A; Day 210
    844.29 (86.4 to 8250)
    205.49 (55.98 to 754.32)
    429.93 (183.37 to 1008.01)
    15.42 (7.11 to 33.45)
        Toxin B; Day 0
    110.73 (11.36 to 1079.55)
    12.77 (6.12 to 26.64)
    26.14 (9.92 to 68.9)
    20.34 (7.02 to 58.94)
        Toxin B; Day 7
    203.07 (13.29 to 3103.27)
    13.36 (5.96 to 29.98)
    51.98 (14.73 to 183.37)
    24.11 (7.32 to 79.49)
        Toxin B; Day 14
    1550.93 (20.37 to 118083)
    60.18 (4.28 to 846.11)
    133.03 (23.33 to 758.68)
    25.66 (7.28 to 90.43)
        Toxin B; Day 28
    1858.33 (20.27 to 170365.2)
    52.09 (4.25 to 638.74)
    123.47 (25.07 to 607.98)
    27.07 (7.78 to 94.13)
        Toxin B; Day 42
    4201.6 (182.78 to 96582.08)
    180 (20.57 to 1575.05)
    252.09 (65.76 to 966.31)
    25.3 (7.39 to 86.7)
        Toxin B; Day 91
    5226.74 (94.74 to 288340.9)
    139.72 (18.74 to 1041.67)
    223.76 (63.69 to 786.15)
    26.06 (8.54 to 79.5)
        Toxin B; Day 210
    1554.39 (46.66 to 51777.55)
    182.08 (20.69 to 1602.57)
    298.34 (90.78 to 980.55)
    31.32 (9.17 to 107.03)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Subjects Aged 65 Years and Older with Clostridium difficile Infection

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    End point title
    Geometric Mean Titers of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Subjects Aged 65 Years and Older with Clostridium difficile Infection
    End point description
    Anti-toxin A and B IgG antibodies were detected using toxin neutralization assay (TNA).
    End point type
    Secondary
    End point timeframe
    Day 0, 7, 14, 28, 42, 91, and 210
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    8
    7
    15
    14
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Toxin A; Day 0
    9.75 (6.11 to 15.58)
    8 (8 to 8)
    12.43 (6.44 to 23.99)
    16.41 (7.05 to 38.21)
        Toxin A; Day 7
    9.93 (5.96 to 16.54)
    10.36 (5.5 to 19.53)
    12.38 (6.52 to 23.48)
    21.91 (9.83 to 48.81)
        Toxin A; Day 14
    23.04 (2.99 to 177.47)
    40.17 (2.21 to 728.8)
    32.65 (10.52 to 101.37)
    21.65 (10.39 to 45.11)
        Toxin A; Day 28
    89.78 (3.88 to 2079.1)
    28.73 (1.91 to 431.65)
    50.09 (16.68 to 150.42)
    20.18 (9.56 to 42.61)
        Toxin A; Day 42
    217.07 (22.36 to 2107.79)
    446.52 (37.75 to 5282.22)
    305.49 (81.86 to 1140.03)
    16.59 (8.07 to 34.11)
        Toxin A; Day 91
    157.01 (11.55 to 2134.8)
    191.01 (37.19 to 981.1)
    226.42 (70.16 to 730.78)
    15.63 (7.95 to 30.7)
        Toxin A; Day 210
    186.64 (15.84 to 2198.69)
    185.94 (35.86 to 964.16)
    173.18 (51.16 to 586.2)
    21.14 (10.74 to 41.61)
        Toxin B; Day 0
    22.25 (1.98 to 249.97)
    9.41 (6.32 to 14.02)
    15.4 (7.8 to 30.42)
    12.57 (4.7 to 33.64)
        Toxin B; Day 7
    21.95 (2.02 to 238.58)
    15.9 (2.96 to 85.29)
    19.52 (9.01 to 42.31)
    20.25 (5.18 to 79.13)
        Toxin B; Day 14
    25.38 (1.5 to 428.18)
    66.31 (1.76 to 2500.04)
    55.38 (11.13 to 275.6)
    19.6 (5.24 to 73.26)
        Toxin B; Day 28
    29.92 (1.01 to 888.05)
    59.69 (1.75 to 2036.78)
    49.08 (10.42 to 231.11)
    27.29 (6.04 to 123.25)
        Toxin B; Day 42
    31.35 (2.53 to 388.47)
    295.06 (10.28 to 8466.65)
    56.88 (10.59 to 305.54)
    14.7 (5.31 to 40.67)
        Toxin B; Day 91
    30.15 (1.78 to 511.7)
    151.81 (13.4 to 1719.59)
    94.99 (23.8 to 379.11)
    13.81 (5.16 to 36.95)
        Toxin B; Day 210
    32.29 (2.5 to 417.64)
    137.66 (10.14 to 1868.39)
    72.96 (16.82 to 316.45)
    28.74 (6.72 to 122.89)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Seropositive Subjects with Clostridium difficile Infection

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    End point title
    Geometric Mean Titers of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Seropositive Subjects with Clostridium difficile Infection
    End point description
    Anti-toxin A and B IgG antibodies were detected using toxin neutralization assay (TNA).
    End point type
    Secondary
    End point timeframe
    Day 0, 7, 14, 28, 42, 91, and 210
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    5
    3
    10
    6
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Toxin A; Day 0
    67.09 (23.95 to 187.9)
    64.51 (13.4 to 310.62)
    123.31 (48.21 to 315.37)
    107.11 (37.07 to 309.44)
        Toxin A; Day 7
    408.47 (58.97 to 2829.51)
    210.86 (0 to 210.86)
    352.01 (55.45 to 2234.71)
    152.18 (72.38 to 319.96)
        Toxin A; Day 14
    19521.78 (3681.49 to 103517.8)
    1163.36 (0 to 1163.36)
    1097.28 (102.48 to 11748.58)
    122.35 (56.47 to 265.12)
        Toxin A; Day 28
    17523.31 (10850.72 to 28299.17)
    853.73 (0 to 853.73)
    642.72 (76.32 to 5412.87)
    85.91 (32.26 to 228.81)
        Toxin A; Day 42
    12976.13 (8976.73 to 18757.37)
    1684.21 (0 to 1684.21)
    2298.39 (486.15 to 10866.11)
    85.2 (28.22 to 257.2)
        Toxin A; Day 91
    8599.81 (2154.22 to 34331.03)
    825.84 (0 to 825.84)
    926.01 (179.95 to 4765.23)
    63.24 (13.87 to 288.37)
        Toxin A; Day 210
    3220.55 (2652.22 to 3910.65)
    622.97 (4.98 to 77925.37)
    1111.46 (183.57 to 6729.6)
    29.47 (6.41 to 135.43)
        Toxin B; Day 0
    962.39 (73.17 to 12658.38)
    55.63 (5.6 to 552.53)
    270.87 (71.54 to 1025.52)
    1081.15 (36.51 to 32019.8)
        Toxin B; Day 7
    1948.79 (256.3 to 14817.98)
    219.52 (5.73 to 8415.53)
    843.31 (242.91 to 2927.79)
    2365.82 (96.07 to 58261.18)
        Toxin B; Day 14
    22395.3 (9272.01 to 54092.82)
    43468.98 (6655.89 to 283891.6)
    8115.79 (1427.12 to 46153.08)
    2169.08 (90.05 to 52247.36)
        Toxin B; Day 28
    26898.48 (8155.45 to 88717.11)
    30575 (2499.59 to 373993.2)
    7944.79 (1437.14 to 43920.4)
    2095.95 (83.9 to 52361.6)
        Toxin B; Day 42
    22981.2 (7006.12 to 75382)
    20741.22 (2631.92 to 163454.2)
    10200.68 (2361.41 to 44064.21)
    1484.04 (87.83 to 25074.91)
        Toxin B; Day 91
    13121.43 (2070.41 to 83158.23)
    10631.78 (334.25 to 338170.6)
    4234.13 (907.02 to 19765.66)
    1243.01 (92.03 to 16788.75)
        Toxin B; Day 210
    8086.41 (1454.09 to 44969.8)
    12036.97 (390.54 to 370999.1)
    4540.73 (1249.33 to 16503.45)
    249.12 (16.64 to 3729.11)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Seronegative Subjects with Clostridium difficile Infection

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    End point title
    Geometric Mean Titers of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Seronegative Subjects with Clostridium difficile Infection
    End point description
    Anti-toxin A and B IgG antibodies were detected using toxin neutralization assay (TNA).
    End point type
    Secondary
    End point timeframe
    Day 0, 7, 14, 28, 42, 91, and 210
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    9
    14
    28
    28
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Toxin A; Day 0
    8 (8 to 8)
    8 (8 to 8)
    8 (8 to 8)
    8 (8 to 8)
        Toxin A; Day 7
    8 (8 to 8)
    9.74 (7.24 to 13.1)
    8 (8 to 8)
    8.93 (7.87 to 10.13)
        Toxin A; Day 14
    13.03 (5.97 to 28.45)
    40.09 (9.33 to 172.37)
    25.41 (14.25 to 45.3)
    9.38 (7.78 to 11.31)
        Toxin A; Day 28
    29.61 (8.55 to 102.53)
    47.43 (10.7 to 210.21)
    47.18 (23.31 to 95.5)
    10.84 (7.54 to 15.57)
        Toxin A; Day 42
    117.76 (35.89 to 386.36)
    337.01 (91.41 to 1242.56)
    308.29 (149.76 to 634.62)
    9.77 (7.58 to 12.59)
        Toxin A; Day 91
    70.48 (17.09 to 290.75)
    190.88 (71.25 to 511.36)
    234.15 (112.46 to 487.54)
    11.69 (7.63 to 17.9)
        Toxin A; Day 210
    107.74 (21.82 to 531.92)
    165.44 (61.77 to 443.11)
    244.88 (115.83 to 517.72)
    14.86 (8.11 to 27.21)
        Toxin B; Day 0
    8 (8 to 8)
    8 (8 to 8)
    8 (8 to 8)
    8 (8 to 8)
        Toxin B; Day 7
    8 (8 to 8)
    8 (8 to 8)
    9.85 (7.02 to 13.82)
    8 (8 to 8)
        Toxin B; Day 14
    8 (8 to 8)
    13.78 (5.93 to 32.02)
    15.73 (7.87 to 31.45)
    8 (8 to 8)
        Toxin B; Day 28
    8 (8 to 8)
    12.74 (6.15 to 26.4)
    16.24 (8.94 to 29.48)
    9.34 (7.37 to 11.83)
        Toxin B; Day 42
    20 (7.32 to 54.6)
    67.5 (22.58 to 201.79)
    35.87 (18.15 to 70.9)
    8.63 (7.38 to 10.11)
        Toxin B; Day 91
    16.32 (4.4 to 60.57)
    53.42 (22.11 to 129.08)
    56.07 (27.22 to 115.49)
    9.25 (7.42 to 11.52)
        Toxin B; Day 210
    21.88 (6.59 to 72.72)
    55.52 (22.62 to 136.26)
    65.28 (30.47 to 139.82)
    15.83 (6.93 to 36.17)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Clostridium difficile Infection Reporting Solicited Injection Site or Systemic Reaction Following First Vaccination with Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or a Placebo

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    End point title
    Percentage of Subjects with Clostridium difficile Infection Reporting Solicited Injection Site or Systemic Reaction Following First Vaccination with Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or a Placebo
    End point description
    Solicited injection site: Pain, Redness, Swelling, Tenderness, and Itching. Solicited systemic reactions: Fever, Bowel movements, Loose/watery bowel, Abdominal pain, Vomiting, Appetite lost, Headache, Malaise, and Myalgia. Grade 3 Solicited Injection site reactions: Pain, Tenderness, and Itching – Significant, prevents daily activity; Redness and Swelling - >10 cm. Grade 3 Solicited systemic reactions: Fever - ≥39˚C or ≥102.1˚F; Bowel movements – not applicable; Loose/watery bowel - >6 loose/watery bowel movements; Abdominal pain, Vomiting, Appetite lost, Headache, Malaise, and Myalgia – Significant, prevents daily activities. Analysis was in the Safety analysis set.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-injection) up to Day 6 post-injection 1
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    17
    18
    40
    38
    Units: Percentage of subjects
    number (not applicable)
        Injection site Pain
    43.8
    37.5
    38.9
    15.2
        Grade 3 Injection site Pain
    0
    0
    0
    0
        Injection site Redness
    0
    6.3
    8.3
    3
        Grade 3 Injection site Redness
    0
    0
    0
    0
        Injection site Swelling
    0
    0
    8.3
    3
        Grade 3 Injection site Swelling
    0
    0
    0
    0
        Injection site Tenderness
    68.8
    37.5
    55.6
    15.2
        Grade 3 Injection site Tenderness
    0
    0
    5.6
    0
        Injection site Itching
    0
    12.5
    8.3
    0
        Grade 3 Injection site Itching
    0
    0
    0
    0
        Fever
    6.3
    6.3
    8.3
    9.1
        Grade 3 Fever
    0
    0
    2.8
    6.1
        Bowel movements
    100
    100
    100
    97
        Bowel movements; Yes
    100
    100
    100
    97
        Loose/watery bowel
    81.3
    75
    66.7
    63.6
        Grade 3 Loose/watery bowel
    6.3
    0
    0
    9.1
        Abdominal pain
    56.3
    37.5
    41.7
    39.4
        Grade 3 Abdominal pain
    12.5
    0
    5.6
    6.1
        Vomiting
    6.3
    6.3
    0
    6.1
        Grade 3 Vomiting
    6.3
    0
    0
    0
        Appetite lost
    31.3
    6.3
    19.4
    15.2
        Grade 3 Appetite lost
    6.3
    0
    2.8
    0
        Headache
    37.5
    12.5
    19.4
    9.1
        Grade 3 Headache
    0
    0
    0
    0
        Malaise
    6.3
    6.3
    19.4
    18.2
        Grade 3 Malaise
    0
    0
    0
    3
        Myalgia
    60
    0
    64.3
    44.4
        Grade 3 Myalgia
    0
    0
    0
    11.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Clostridium difficile Infection Reporting Solicited Injection Site or Systemic Reaction Following Second Vaccination with Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or a Placebo

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    End point title
    Percentage of Subjects with Clostridium difficile Infection Reporting Solicited Injection Site or Systemic Reaction Following Second Vaccination with Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or a Placebo
    End point description
    Solicited injection site: Pain, Redness, Swelling, Tenderness, and Itching. Solicited systemic reactions: Fever, Bowel movements, Loose/watery bowel, Abdominal pain, Vomiting, Appetite lost, Headache, Malaise, and Myalgia. Grade 3 Solicited Injection site reactions: Pain, Tenderness, and Itching – Significant, prevents daily activity; Redness and Swelling - >10 cm. Grade 3 Solicited systemic reactions: Fever - ≥39˚C or ≥102.1˚F; Bowel movements – not applicable; Loose/watery bowel - >6 loose/watery bowel movements; Abdominal pain, Vomiting, Appetite lost, Headache, Malaise, and Myalgia – Significant, prevents daily activities. Analysis was in the Safety analysis set.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-injection) up to Day 6 post-injection 2
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    15
    16
    34
    37
    Units: Percentage of subjects
    number (not applicable)
        Injection site Pain
    33.3
    37.5
    44.1
    6.5
        Grade 3 Injection site Pain
    0
    0
    8.8
    3.2
        Injection site Redness
    0
    18.8
    5.9
    0
        Grade 3 Injection site Redness
    0
    0
    0
    0
        Injection site Swelling
    0
    0
    11.8
    0
        Grade 3 Injection site Swelling
    0
    0
    0
    0
        Injection site Tenderness
    60
    43.8
    52.9
    6.5
        Grade 3 Injection site Tenderness
    0
    0
    2.9
    0
        Injection site Itching
    6.7
    12.5
    8.8
    0
        Grade 3 Injection site Itching
    0
    0
    0
    0
        Fever
    6.7
    12.5
    2.9
    6.3
        Grade 3 Fever
    0
    0
    2.9
    3.1
        Bowel movements
    100
    100
    100
    100
        Bowel movements; Yes
    100
    100
    100
    100
        Loose/watery bowel
    40
    87.5
    58.8
    62.5
        Grade 3 Loose/watery bowel
    6.7
    6.3
    2.9
    3.1
        Abdominal pain
    46.7
    43.8
    41.2
    34.4
        Grade 3 Abdominal pain
    13.3
    6.3
    5.9
    3.1
        Vomiting
    6.7
    0
    5.9
    6.3
        Grade 3 Vomiting
    6.7
    0
    0
    3.1
        Appetite lost
    20
    0
    23.5
    6.3
        Grade 3 Appetite lost
    6.7
    0
    2.9
    0
        Headache
    46.7
    18.8
    20.6
    9.4
        Grade 3 Headache
    6.7
    0
    2.9
    3.1
        Malaise
    6.7
    6.3
    20.6
    12.5
        Grade 3 Malaise
    6.7
    0
    0
    0
        Myalgia
    40
    50
    64.3
    42.9
        Grade 3 Myalgia
    20
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Clostridium difficile Infection Reporting Solicited Injection Site or Systemic Reaction Following Third Vaccination with Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or a Placebo

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    End point title
    Percentage of Subjects with Clostridium difficile Infection Reporting Solicited Injection Site or Systemic Reaction Following Third Vaccination with Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or a Placebo
    End point description
    Solicited injection site: Pain, Redness, Swelling, Tenderness, and Itching. Solicited systemic reactions: Fever, Bowel movements, Loose/watery bowel, Abdominal pain, Vomiting, Appetite lost, Headache, Malaise, and Myalgia. Grade 3 Solicited Injection site reactions: Pain, Tenderness, and Itching – Significant, prevents daily activity; Redness and Swelling - >10 cm. Grade 3 Solicited systemic reactions: Fever - ≥39˚C or ≥102.1˚F; Bowel movements – not applicable; Loose/watery bowel - >6 loose/watery bowel movements; Abdominal pain, Vomiting, Appetite lost, Headache, Malaise, and Myalgia – Significant, prevents daily activities. Analysis was in the Safety analysis set.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-injection) up to Day 6 post-injection 3
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    12
    16
    33
    32
    Units: Percentage of subjects
    number (not applicable)
        Injection site Pain
    25
    43.8
    39.4
    3.1
        Grade 3 Injection site Pain
    0
    0
    0
    0
        Injection site Redness
    8.3
    18.8
    15.2
    0
        Grade 3 Injection site Redness
    0
    0
    3
    0
        Injection site Swelling
    8.3
    6.3
    15.2
    0
        Grade 3 Injection site Swelling
    0
    0
    6.1
    0
        Injection site Tenderness
    33.3
    50
    51.5
    9.4
        Grade 3 Injection site Tenderness
    0
    0
    6.1
    0
        Injection site Itching
    16.7
    0
    12.1
    3.1
        Grade 3 Injection site Itching
    0
    0
    0
    0
        Fever
    0
    0
    6.1
    6.3
        Grade 3 Fever
    0
    0
    3
    0
        Bowel movements
    100
    100
    100
    93.8
        Bowel movements; Yes
    100
    100
    100
    93.8
        Loose/watery bowel
    41.7
    50
    33.3
    37.5
        Grade 3 Loose/watery bowel
    0
    6.3
    0
    3.1
        Abdominal pain
    41.7
    43.8
    36.4
    15.6
        Grade 3 Abdominal pain
    8.3
    6.3
    6.1
    3.1
        Vomiting
    16.7
    0
    6.1
    0
        Grade 3 Vomiting
    8.3
    0
    0
    0
        Appetite lost
    33.3
    6.3
    18.2
    6.3
        Grade 3 Appetite lost
    8.3
    0
    3
    0
        Headache
    16.7
    6.3
    18.2
    9.4
        Grade 3 Headache
    0
    0
    3
    0
        Malaise
    16.7
    0
    21.2
    9.4
        Grade 3 Malaise
    0
    0
    3
    0
        Myalgia
    20
    0
    71.4
    30
        Grade 3 Myalgia
    20
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Geometric Mean Fold Rise in Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Subjects with Clostridium difficile Infection

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    End point title
    Geometric Mean Fold Rise in Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Subjects with Clostridium difficile Infection
    End point description
    Anti-toxin A and B IgG antibodies were detected using toxin antibody enzyme-linked immunosorbent assay (ELISA). Analysis was in the Intent-to-treat analysis set for immunogenicity.
    End point type
    Secondary
    End point timeframe
    Day 0, 7, 14, 28, 42, 91, and 210
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    14
    17
    37
    34
    Units: Concentrations (EU/mL)
    geometric mean (confidence interval 95%)
        Toxin A IgG; Day 7/Day 0
    1.65 (0.92 to 2.99)
    1.09 (0.98 to 1.21)
    1.25 (0.95 to 1.65)
    1.15 (0.98 to 1.35)
        Toxin A IgG; Day 14/Day 0
    11.66 (2.43 to 55.93)
    6.86 (2.18 to 21.55)
    3.72 (2.18 to 6.37)
    1.21 (0.98 to 1.47)
        Toxin A IgG; Day 14/Day 7
    6.78 (1.85 to 24.82)
    6.26 (2.15 to 18.22)
    3.01 (1.86 to 4.88)
    1.05 (0.95 to 1.16)
        Toxin A IgG; Day 28/Day 0
    24.06 (5.02 to 115.4)
    12.39 (4.03 to 38.06)
    6.86 (4.01 to 11.73)
    1.39 (0.95 to 2.02)
        Toxin A IgG; Day28/Day 7
    13.37 (3.3 to 54.21)
    11.31 (3.91 to 32.72)
    5.66 (3.35 to 9.56)
    1.18 (0.9 to 1.55)
        Toxin A IgG; Day 28/Day 14
    1.76 (0.95 to 3.28)
    1.81 (1.15 to 2.85)
    1.84 (1.21 to 2.81)
    1.1 (0.87 to 1.38)
        Toxin A IgG; Day 42/Day 0
    45.9 (15.32 to 137.51)
    43.29 (16.54 to 113.29)
    52.96 (29.41 to 95.35)
    1.13 (0.94 to 1.37)
        Toxin A IgG; Day 42/Day 28
    2.17 (0.92 to 5.12)
    3.48 (1.76 to 6.87)
    6.98 (4.13 to 11.78)
    0.94 (0.88 to 1.01)
        Toxin A IgG; Day 91/Day 0
    19.02 (5.84 to 61.93)
    24.05 (10.37 to 55.79)
    19.9 (11.76 to 33.67)
    1.33 (0.89 to 1.99)
        Toxin A IgG; Day 210/Day 0
    8.65 (3.04 to 24.61)
    6.62 (3.01 to 14.57)
    7.69 (4.43 to 13.34)
    1.26 (0.82 to 1.96)
        Toxin B IgG; Day 7/Day 0
    1.35 (1.02 to 1.77)
    1.33 (0.86 to 2.07)
    1.91 (1.21 to 3.02)
    1.25 (0.92 to 1.71)
        Toxin B IgG; Day 14/Day 0
    4.23 (1.72 to 10.39)
    9.66 (2.43 to 38.48)
    6.7 (3.13 to 14.35)
    1.39 (0.99 to 1.95)
        Toxin B IgG; Day 14/Day 7
    3.07 (1.44 to 6.58)
    7.12 (2.16 to 23.4)
    3.56 (2.03 to 6.23)
    1.1 (0.98 to 1.24)
        Toxin B IgG; Day 28/Day 0
    5.37 (1.74 to 16.52)
    26.98 (8.62 to 84.5)
    11.48 (5.93 to 22.22)
    2.25 (1.18 to 4.27)
        Toxin B IgG; Day 28/Day 7
    3.8 (1.44 to 10.02)
    19.87 (7.63 to 51.76)
    6.02 (3.49 to 10.38)
    1.69 (0.98 to 2.9)
        Toxin B IgG; Day 28/Day 14
    1.23 (0.74 to 2.04)
    2.79 (1.53 to 5.11)
    1.71 (1.2 to 2.45)
    1.52 (0.93 to 2.48)
        Toxin B IgG; Day 42/Day 0
    11.69 (3.46 to 39.49)
    146.08 (57.98 to 368.05)
    40.05 (20.49 to 78.27)
    2.1 (1.19 to 3.71)
        Toxin B IgG; Day 42/Day 28
    2.25 (1.06 to 4.77)
    6.03 (2.13 to 17.06)
    3.21 (1.97 to 5.22)
    1.13 (0.93 to 1.37)
        Toxin B IgG; Day 91/Day 0
    5.47 (1.33 to 22.44)
    58.14 (22.42 to 150.75)
    19.08 (9.84 to 36.98)
    2.49 (1.28 to 4.84)
        Toxin B IgG; Day 210/Day 0
    3.7 (1.15 to 11.91)
    13.72 (5.39 to 34.93)
    9.33 (5.14 to 16.95)
    1.77 (0.75 to 4.16)
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentrations of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Subjects with Clostridium difficile Infection

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    End point title
    Geometric Mean Concentrations of Anti-toxin A and B IgG After A Third Dose of Clostridium Difficile Toxoid Vaccine (ACAM-CDIFFTM) or A Placebo in Subjects with Clostridium difficile Infection
    End point description
    Anti-toxin A and B IgG antibodies were detected using toxin antibody enzyme-linked immunosorbent assay (ELISA). Analysis was in the Intent-to-treat analysis set for efficacy.
    End point type
    Secondary
    End point timeframe
    Day 0, 7, 14, 28, 42, 91, and 210
    End point values
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Number of subjects analysed
    14
    17
    37
    34
    Units: Concentrations (EU/mL)
    geometric mean (confidence interval 95%)
        Toxin A IgG; Day 0
    1.04 (0.7 to 1.53)
    0.78 (0.71 to 0.86)
    0.99 (0.73 to 1.33)
    1.01 (0.78 to 1.3)
        Toxin A IgG; Day 7
    1.8 (0.7 to 4.68)
    0.93 (0.73 to 1.18)
    1.32 (0.82 to 2.14)
    1.3 (0.94 to 1.81)
        Toxin A IgG; Day 14
    17.07 (2.69 to 108.18)
    8.32 (2.35 to 29.41)
    5.1 (2.49 to 10.43)
    1.38 (0.93 to 2.03)
        Toxin A IgG; Day 28
    37.26 (5.83 to 238.2)
    16.39 (4.86 to 55.3)
    10.4 (5.39 to 20.06)
    1.49 (0.91 to 2.46)
        Toxin A IgG; Day 42
    78.88 (22.06 to 282.02)
    65.21 (24.93 to 170.59)
    87.65 (47.97 to 160.16)
    1.1 (0.78 to 1.54)
        Toxin A IgG; Day 91
    30.58 (7.95 to 117.56)
    34.68 (14.18 to 84.82)
    30.55 (17.66 to 52.86)
    1.44 (0.89 to 2.34)
        Toxin A IgG; Day 210
    12.97 (3.72 to 45.21)
    9.1 (3.81 to 21.71)
    10.75 (5.73 to 20.17)
    1.46 (0.9 to 2.36)
        Toxin B IgG; Day 0
    1.91 (0.46 to 7.86)
    0.67 (0.43 to 1.05)
    1.54 (0.83 to 2.87)
    1.17 (0.54 to 2.57)
        Toxin B IgG; Day 7
    2.7 (0.59 to 12.43)
    0.97 (0.48 to 1.97)
    3.26 (1.44 to 7.38)
    1.74 (0.7 to 4.33)
        Toxin B IgG; Day 14
    10.69 (1.46 to 78.49)
    8.35 (1.44 to 48.39)
    12.07 (4.06 to 35.89)
    2.04 (0.79 to 5.31)
        Toxin B IgG; Day 28
    15.81 (2.13 to 117.54)
    28.96 (7.31 to 114.75)
    24.12 (10.25 to 56.77)
    3.7 (1.33 to 10.29)
        Toxin B IgG; Day 42
    34.67 (6.22 to 193.19)
    167.46 (62.38 to 449.54)
    85.21 (42.95 to 169.05)
    3.22 (1.19 to 8.75)
        Toxin B IgG; Day 91
    18.27 (2.66 to 125.7)
    65.16 (22.59 to 187.95)
    40.01 (20.61 to 77.69)
    3.74 (1.43 to 9.77)
        Toxin B IgG; Day 210
    10.2 (1.98 to 52.49)
    15.01 (4.75 to 47.45)
    18.6 (9.05 to 38.22)
    2.94 (1.21 to 7.17)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data were collected from Day 0 to Day 91 after the first vaccination.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    50 µg + AlOH
    Reporting group description
    Subjects who received 3 injections of 50 µg ACAM-CDIFF vaccine plus aluminum hydroxide (AlOH) adjuvant (400 μg aluminum per dose) administered on Days 0, 7, and 28.

    Reporting group title
    100 µg
    Reporting group description
    Subjects who received 3 injections of 100 µg ACAM-CDIFF Vaccine (no adjuvant) administered on Days 0, 7, and 28.

    Reporting group title
    100 µg + AlOH
    Reporting group description
    Subjects who received 3 injections of 100 µg ACAM-CDIFF Vaccine plus AlOH adjuvant (400 μg aluminum per dose) administered on Days 0, 7, and 28.

    Reporting group title
    Placebo
    Reporting group description
    Subjects who received 3 injections of placebo vaccine (0.9% normal saline) administered on Days 0, 7, and 28.

    Serious adverse events
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 17 (52.94%)
    3 / 18 (16.67%)
    12 / 40 (30.00%)
    13 / 38 (34.21%)
         number of deaths (all causes)
    3
    1
    1
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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
    Peripheral ischaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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 stenosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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
    Metastases to liver
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (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 / 1
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (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
    Multi-organ failure
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (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
    Alcoholism
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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
    Anxiety
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (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
    Mental status changes
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (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
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (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
    Graft thrombosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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
    Hip fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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
    Incisional hernia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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
    Multiple fractures
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (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
    Ulna fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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 graft occlusion
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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
    Investigations
    Blood potassium increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (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
    Cardiac arrest
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (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
    Congenital, familial and genetic disorders
    Cystic fibrosis lung
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (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
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (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
    Nervous system disorders
    Complex partial seizures
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (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
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (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
    Abdominal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute abdomen
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (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
    Crohn's disease
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (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
    Diarrhoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (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
    Diverticulum
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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
    Gastritis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (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
    Intestinal obstruction
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (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
    Pancreatitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (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
    Rectal haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (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
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (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
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (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
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (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
    Infections and infestations
    Abscess fungal
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (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
    Biliary sepsis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (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
    Bronchopneumonia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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 / 1
    Catheter related infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (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
    Cellulitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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
    Clostridial infection
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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
    Gangrene
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (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
    Gastroenteritis pseudomonas
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (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
    Implant site infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (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
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (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
    Pneumonia
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 18 (11.11%)
    3 / 40 (7.50%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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
    Septic shock
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    0 / 38 (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
    Urosepsis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    50 µg + AlOH 100 µg 100 µg + AlOH Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 17 (94.12%)
    16 / 18 (88.89%)
    36 / 40 (90.00%)
    32 / 38 (84.21%)
    General disorders and administration site conditions
    Discomfort
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    3 / 38 (7.89%)
         occurrences all number
    1
    1
    1
    9
    Fatigue
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Injection site erythema
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injection site haematoma
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Injection site induration
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injection site warmth
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Multi-organ failure
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Pyrexia
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 18 (0.00%)
    3 / 40 (7.50%)
    0 / 38 (0.00%)
         occurrences all number
    2
    0
    3
    0
    Vaccination site pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injection site pain
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    7 / 16 (43.75%)
    7 / 16 (43.75%)
    15 / 34 (44.12%)
    5 / 33 (15.15%)
         occurrences all number
    7
    7
    15
    5
    Injection site redness
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    1 / 12 (8.33%)
    3 / 16 (18.75%)
    5 / 33 (15.15%)
    1 / 33 (3.03%)
         occurrences all number
    1
    3
    5
    1
    Injection site swelling
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    1 / 12 (8.33%)
    1 / 16 (6.25%)
    5 / 33 (15.15%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    5
    1
    Injection site tenderness
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    11 / 16 (68.75%)
    8 / 16 (50.00%)
    20 / 36 (55.56%)
    5 / 33 (15.15%)
         occurrences all number
    11
    8
    20
    5
    Injection site itching
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    2 / 12 (16.67%)
    2 / 16 (12.50%)
    4 / 33 (12.12%)
    1 / 32 (3.13%)
         occurrences all number
    2
    2
    4
    1
    Fever
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    1 / 15 (6.67%)
    2 / 16 (12.50%)
    3 / 36 (8.33%)
    3 / 33 (9.09%)
         occurrences all number
    1
    2
    3
    3
    Abdominal pain
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    9 / 16 (56.25%)
    7 / 16 (43.75%)
    15 / 36 (41.67%)
    13 / 33 (39.39%)
         occurrences all number
    9
    7
    15
    13
    Malaise
    alternative assessment type: Systematic
         subjects affected / exposed [8]
    2 / 12 (16.67%)
    1 / 16 (6.25%)
    7 / 33 (21.21%)
    6 / 33 (18.18%)
         occurrences all number
    2
    1
    7
    6
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    2
    1
    Insomnia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Restlessness
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Nipple pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Electrocardiogram change
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    1
    0
    0
    1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    2 / 38 (5.26%)
         occurrences all number
    0
    0
    1
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    2 / 40 (5.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Pleural effusion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Tremor
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed [9]
    7 / 15 (46.67%)
    3 / 16 (18.75%)
    7 / 34 (20.59%)
    3 / 32 (9.38%)
         occurrences all number
    7
    3
    7
    3
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Constipation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    3 / 40 (7.50%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    3
    1
    Crohn's disease
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 18 (0.00%)
    7 / 40 (17.50%)
    3 / 38 (7.89%)
         occurrences all number
    4
    0
    9
    6
    Haematochezia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Intestinal obstruction
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    5 / 40 (12.50%)
    3 / 38 (7.89%)
         occurrences all number
    2
    0
    6
    3
    Oral pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Proctalgia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Bowel movements
    alternative assessment type: Systematic
         subjects affected / exposed [10]
    16 / 16 (100.00%)
    16 / 16 (100.00%)
    36 / 36 (100.00%)
    32 / 32 (100.00%)
         occurrences all number
    16
    16
    36
    32
    Loose/watery bowel
    alternative assessment type: Systematic
         subjects affected / exposed [11]
    13 / 16 (81.25%)
    14 / 16 (87.50%)
    24 / 36 (66.67%)
    21 / 33 (63.64%)
         occurrences all number
    13
    14
    24
    21
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed [12]
    2 / 12 (16.67%)
    1 / 16 (6.25%)
    2 / 33 (6.06%)
    2 / 32 (6.25%)
         occurrences all number
    2
    1
    2
    2
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Urinary retention
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Skin ulcer
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Back pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    3 / 40 (7.50%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Myalgia
    alternative assessment type: Systematic
         subjects affected / exposed [13]
    3 / 5 (60.00%)
    1 / 2 (50.00%)
    10 / 14 (71.43%)
    4 / 9 (44.44%)
         occurrences all number
    3
    1
    10
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 17 (11.76%)
    3 / 18 (16.67%)
    2 / 40 (5.00%)
    4 / 38 (10.53%)
         occurrences all number
    4
    3
    2
    7
    Hypokalaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    3 / 40 (7.50%)
    3 / 38 (7.89%)
         occurrences all number
    2
    0
    3
    4
    Metabolic acidosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Appetite lost
    alternative assessment type: Systematic
         subjects affected / exposed [14]
    4 / 12 (33.33%)
    1 / 16 (6.25%)
    8 / 34 (23.53%)
    5 / 33 (15.15%)
         occurrences all number
    4
    1
    8
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Catheter related infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    0
    0
    2
    Clostridial infection
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    1 / 38 (2.63%)
         occurrences all number
    2
    0
    1
    1
    Ear infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    3 / 38 (7.89%)
         occurrences all number
    1
    1
    1
    3
    Nasopharyngitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    0
    3
    2
    Oral candidiasis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 18 (11.11%)
    4 / 40 (10.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    2
    6
    0
    Rhinitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Septic shock
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 18 (11.11%)
    7 / 40 (17.50%)
    6 / 38 (15.79%)
         occurrences all number
    2
    3
    8
    6
    Urinary tract infection fungal
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [11] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [12] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [13] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [14] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Oct 2008
    Suspected unexpected serious adverse events and their definitions were added.
    06 Feb 2009
    Primary end point updated to compare the event rate of CDI in groups assigned to ACAM-CDIFF vaccine (pooled groups) versus placebo in the 9-week period after the third dose of study vaccine (Study Days 29 to 91) in subjects with a first episode of laboratory confirmed CDI up to 10 days prior to the first dose of study vaccine, receiving antibiotic standard of care; safety endpoint updated to compare the frequency of local and systemic adverse events (AEs) and serious adverse events (SAEs), new laboratory abnormalities, reported in subjects assigned to ACAM-CDIFF vaccine (pooled) versus placebo since first dose of study vaccine until day 210; clarified definition to "a change in bowel habit with passage of 2 or more loose stools within 24 hours (that conforms to the shape of the container it is placed into)”; exclusion criteria were revised; an Independent Data Monitoring Committee (IDMC) was added at the request of FDA to ensure increase safety monitoring; added that a related fatal event would trigger an immediate pause of the study and investigation by the IDMC; Clarification about treatment and documentation of CDI recurrences; Replaced a structured interview with questions about symptoms of CDI and AEs through Day 210; Revised definition of causal relationship to study vaccination and toxicity grading scale for local site reactions and systemic reactions. Two interim analyses were proposed.
    31 Mar 2009
    Added that a confirmatory cytotoxicity assay test was required for inclusion and viral serology tests HBsAg and HCV were removed from the study.
    06 May 2009
    Number of clinical sites increased from 70 to 75; increased screening period to within 12 days of administration of the first dose and definition of Clostridium difficile Infection (CDI) refined to: “Primary CDI redefined; modified age range of subjects to allow all adults ≥ 18 years; the cytotoxin assay was defined more clearly; modified/revised some exclusion criteria on: expected mortality, previous CDI events, platelet counts, previous chemotherapy, body mass index, time for completion. Added detailed information concerning the Independent Data Monitoring Committee and their review of safety information; and a proposal for 3 interim analyses in the study.
    15 Jun 2009
    Modified exclusion criterion describing platelet counts (specifically, count should not be < 70,000 cell/mm3).
    20 Aug 2009
    Extended study period to 1.5 years; added a secondary objective; reduced overall study number to 612 subjects, reduced power to 80%, and based on Fisher exact test; changed screening tests to ELISA/EIA or PCR, with cytotoxicity as a confirmatory test; applied randomization and analysis by country; added a rationale for the primary objective; adjusted the clinical diagnostic criteria to be more stringent, in accordance with national guidelines, modified or added 3 exclusion criteria. Added calculation of BMI; clarified reporting of serious adverse events; and replaced the Toxicity Grading Scale for solicited reactions with the one used by Sanofi Pasteur.
    19 Nov 2009
    Added geometric mean titers to the immunogenicity evaluations and allowed pneumococcal vaccine within 30 days before or after trial vaccination.
    30 Apr 2010
    Stopped enrollment in the UK; changed the statistical method to the Fisher exact test for comparison of the CDI event rates; changed analysis of seroconversion from Chi-Square or Fisher test to the Newcombe-Wilson without continuity correction; revised inclusion and exclusion criteria; and specified that the second IDMC meeting would occur after the first 38 subjects were enrolled and received 2 doses of vaccine.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 Dec 2010
    This study was halted due to operational futility before the planned number of subjects was enrolled. Significant efforts were made by the Sponsor to facilitate enrollment with the study sites, including amending the protocol to relax inclusion/exclusion criteria based on screening failures and discussion with key opinion leaders, amending the protocol to use paper diaries in place of the e-diaries, and facilitating communication with investigators and site staff. Despite these efforts, subject accrual remained low and enrollment metrics were not met. Ultimately, the decision was made to terminate subject enrollment.
    -

    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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