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    Clinical Trial Results:
    DOSE-CONFIRMATION, IMMUNOGENICITY AND SAFETY STUDY OF THE CLOSTRIDIUM DIFFICILE VACCINE CANDIDATE VLA84 IN HEALTHY ADULTS AGED 50 YEARS AND OLDER. RANDOMIZED, CONTROLLED, OBSERVER-BLIND PHASE II STUDY.

    Summary
    EudraCT number
    		 2014-003934-22
    Trial protocol
    		 DE  
    Global end of trial date
    15 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jan 2017
    First version publication date
    19 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VLA84-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Valneva Austria GmbH
    Sponsor organisation address
    Campus Vienna Biocenter 3, Vienna, Austria, 1030
    Public contact
    Clinical Operations, Valneva Austria GmbH, 0043 1206200, info@valneva.com
    Scientific contact
    Clinical Operations, Valneva Austria GmbH, 0043 1206200, info@valneva.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
    21 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm the optimal dose and formulation of VLA84 in healthy adults aged ≥50 years
    Protection of trial subjects
    Data Safety Monitoring Board (DSMB) was established to periodically review accruing safety information and if necessary, to determine during ad-hoc meetings whether study or individual subject stopping rules have been met.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 106
    Country: Number of subjects enrolled
    United States: 394
    Worldwide total number of subjects
    500
    EEA total number of subjects
    106
    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)
    250
    From 65 to 84 years
    247
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study participants were recruited via sites' databases and/ or advertisements. Recruitment occurred at three study sites in Germany and seven sites in the US. A total of 509 subjects were recruited (thereof 9 were screening failures) during December 2014 till March 2015.

    Pre-assignment
    Screening details
    		 A total of 509 subjects were screened, thereof 9 were screening failures: 7 were screening failures (inclusion/ exclusion criteria), 1 withdrew consent prior, 1 subject: inability to obtain laboratory blood specimen.

    Period 1
    Period 1 title
    Overall study period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    At each study site there was unblinded site personnel responsible for vaccine preparation; moreover there was an unblinded monitor who was solely responsible for drug accountability. The study sponsor remained blinded until database lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 VLA84 75 µg w/o Alum
    Arm description
    		 At each vaccination day (Day 0, 7 and 28) two injections were administered: 0.75 mL VLA84 w/o Alum and 0.75 mL Placebo
    Arm type
    		 Experimental

    Investigational medicinal product name
    VLA84 w/o Alum
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    VLA 84 w/o Alum: C. difficile vaccine antigen is a recombinant fusion protein, formulated in a buffer without adjuvant. Depending on the assigned treatment group either 0.75 ml (treatment group VLA84 75 μg w/o Alum) or 2x 1.0 ml (treatment group VLA84 200 μg w/o Alum) are administered per vaccination day.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Phosphate Buffered Saline
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects assigned to the placebo group received 2x 1.0 ml placebo per vaccination day.

    Arm title
    		 VLA84 200 μg w/o Alum
    Arm description
    		 At each vaccination day (Day 0, 7 and 28) 2x 1.0 mL VLA84 w/o Alum (i.e. a total of 2 ml) were administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VLA84 w/o Alum
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    VLA 84 w/o Alum: C. difficile vaccine antigen is a recombinant fusion protein, formulated in a buffer without adjuvant. Depending on the assigned treatment group either 0.75 ml (treatment group VLA84 75 μg w/o Alum) or 2x 1.0 ml (treatment group VLA84 200 μg w/o Alum) are administered per vaccination day.

    Arm title
    		 VLA84 200 μg w/ Alum
    Arm description
    		 At each vaccination day (Day 0, 7 and 28) 2x 1.0 mL VLA84 w/ Alum (i.e. a total of 2 ml) were administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VLA84 w/ Alum
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    VLA 84 w/ Alum: C. difficile vaccine antigen is a recombinant fusion protein, formulated in a buffer and adjuvanted with Aluminium Hydroxide. 2x 1.0 ml (treatment group VLA84 200 μg w/ Alum) are administered per vaccination day.

    Arm title
    		 Placebo
    Arm description
    		 At each vaccination day (Day 0, 7 and 28) 2x 1.0 mL placebo (i.e. a total of 2 ml) were administered.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Phosphate Buffered Saline
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects assigned to the placebo group received 2x 1.0 ml placebo per vaccination day.

    Number of subjects in period 1
    		VLA84 75 µg w/o Alum VLA84 200 μg w/o Alum VLA84 200 μg w/ Alum Placebo
    Started
    148
    152
    152
    48
    Day 56
    147
    149
    151
    47
    Completed
    143
    146
    147
    46
    Not completed
    5
    6
    5
    2
         Adverse event, serious fatal
    1
    -
    -
    -
         Moved from study area
    -
    3
    3
    -
         Consent withdrawn by subject
    -
    2
    -
    -
         SUBJECT OUT OF TIME WINDOW AND UNCLEAR
    1
    -
    -
    -
         PATIENT IS IN EXTENDED CARE FACILITY
    -
    -
    1
    -
         Lost to follow-up
    3
    1
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study period
    Reporting group description
    		 -

    Reporting group values
    		 Overall study period Total
    Number of subjects
    		 500 500
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
        50 to < 65 years
    		 250 250
        65 years and older
    		 250 250
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64 ± 9.13 -
    Gender categorical
    Units: Subjects
        Female
    		 268 268
        Male
    		 232 232

    End points

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    End points reporting groups
    Reporting group title
    VLA84 75 µg w/o Alum
    Reporting group description
    		 At each vaccination day (Day 0, 7 and 28) two injections were administered: 0.75 mL VLA84 w/o Alum and 0.75 mL Placebo

    Reporting group title
    VLA84 200 μg w/o Alum
    Reporting group description
    		 At each vaccination day (Day 0, 7 and 28) 2x 1.0 mL VLA84 w/o Alum (i.e. a total of 2 ml) were administered.

    Reporting group title
    VLA84 200 μg w/ Alum
    Reporting group description
    		 At each vaccination day (Day 0, 7 and 28) 2x 1.0 mL VLA84 w/ Alum (i.e. a total of 2 ml) were administered.

    Reporting group title
    Placebo
    Reporting group description
    		 At each vaccination day (Day 0, 7 and 28) 2x 1.0 mL placebo (i.e. a total of 2 ml) were administered.

    Primary: Seroconversion Rate for IgG against both Toxin A and Toxin B on Day 56

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    End point title
    		 Seroconversion Rate for IgG against both Toxin A and Toxin B on Day 56
    End point description
    Seroconversion Rate (SCR): defined as proportion of subjects achieving a ≥4-fold increase in antibody titer from Day 0; per-protocol population was primary analysis population (i.e., excluding subjects with major protocol deviations)
    End point type
    Primary
    End point timeframe
    from Day 0 up to Day 56
    End point values
    		 VLA84 75 µg w/o Alum VLA84 200 μg w/o Alum VLA84 200 μg w/ Alum Placebo
    Number of subjects analysed
    137
    135
    141
    46
    Units: proportion of subjects
    98
    112
    84
    0
    Statistical analysis title
    		 overall comparison of seroconversion rates (SCRs)
    Statistical analysis description
    The primary analysis compared the SCR against both Toxin A and Toxin B in the per-protocol (PP210) population between groups on Day 56, using a Cochran-Mantel-Haenszel (CMH) test stratified by age (50-64 vs. ≥ 65 years). Only in presence of a significant overall effect, pair-wise comparisons between groups using CMH tests stratified by age was presented. As an overall test was produced before pair-wise comparisons were generated, no adjustment for multiple testing was performed.
    Comparison groups
    VLA84 200 μg w/o Alum v VLA84 200 μg w/ Alum v VLA84 75 µg w/o Alum v Placebo
    Number of subjects included in analysis
    459
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - Inferential analysis; Only in presence of a significant overall effect, pair-wise comparisons between groups using CMH tests stratified by age was done. As an overall test was produced before pair-wise comparisons are generated, no adjustment for multiple testing was performed.
    Statistical analysis title
    		 comparison of SCR 75 w/o Alum vs. 200 w/o Alum
    Statistical analysis description
    The primary analysis compared the SCR against both Toxin A and Toxin B in the per-protocol (PP210) population between groups on Day 56, using a Cochran-Mantel-Haenszel (CMH) test stratified by age (50-64 vs. ≥ 65 years). Only in presence of a significant overall effect, pair-wise comparisons between groups using CMH tests stratified by age was presented. As an overall test was produced before pair-wise comparisons were generated, no adjustment for multiple testing was performed.
    Comparison groups
    VLA84 75 µg w/o Alum v VLA84 200 μg w/o Alum
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.0261
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [2] - Inferential analysis; Only in presence of a significant overall effect, pair-wise comparisons between groups using CMH tests stratified by age was done. As an overall test was produced before pair-wise comparisons are generated, no adjustment for multiple testing was performed.
    Statistical analysis title
    		 comparison of SCR 75 w/o Alum vs. 200 w/ Alum
    Statistical analysis description
    The primary analysis compared the SCR against both Toxin A and Toxin B in the per-protocol (PP210) population between groups on Day 56, using a Cochran-Mantel-Haenszel (CMH) test stratified by age (50-64 vs. ≥ 65 years). Only in presence of a significant overall effect, pair-wise comparisons between groups using CMH tests stratified by age was presented. As an overall test was produced before pair-wise comparisons were generated, no adjustment for multiple testing was performed.
    Comparison groups
    VLA84 75 µg w/o Alum v VLA84 200 μg w/ Alum
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.0364
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [3] - Inferential analysis; Only in presence of a significant overall effect, pair-wise comparisons between groups using CMH tests stratified by age was done. As an overall test was produced before pair-wise comparisons are generated, no adjustment for multiple testing was performed.
    Statistical analysis title
    		 comparison of SCR 75 w/o Alum vs. placebo
    Statistical analysis description
    The primary analysis compared the SCR against both Toxin A and Toxin B in the per-protocol (PP210) population between groups on Day 56, using a Cochran-Mantel-Haenszel (CMH) test stratified by age (50-64 vs. ≥ 65 years). Only in presence of a significant overall effect, pair-wise comparisons between groups using CMH tests stratified by age was presented. As an overall test was produced before pair-wise comparisons were generated, no adjustment for multiple testing was performed.
    Comparison groups
    VLA84 75 µg w/o Alum v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [4] - Inferential analysis; Only in presence of a significant overall effect, pair-wise comparisons between groups using CMH tests stratified by age was done. As an overall test was produced before pair-wise comparisons are generated, no adjustment for multiple testing was performed.
    Statistical analysis title
    		 comparison of SCR 200 w/o Alum vs. 200 w/ Alum
    Statistical analysis description
    The primary analysis compared the SCR against both Toxin A and Toxin B in the per-protocol (PP210) population between groups on Day 56, using a Cochran-Mantel-Haenszel (CMH) test stratified by age (50-64 vs. ≥ 65 years). Only in presence of a significant overall effect, pair-wise comparisons between groups using CMH tests stratified by age was presented. As an overall test was produced before pair-wise comparisons were generated, no adjustment for multiple testing was performed.
    Comparison groups
    VLA84 200 μg w/o Alum v VLA84 200 μg w/ Alum
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [5] - Inferential analysis; Only in presence of a significant overall effect, pair-wise comparisons between groups using CMH tests stratified by age was done. As an overall test was produced before pair-wise comparisons are generated, no adjustment for multiple testing was performed.
    Statistical analysis title
    		 comparison of SCR 200 w/o Alum vs. placebo
    Statistical analysis description
    The primary analysis compared the SCR against both Toxin A and Toxin B in the per-protocol (PP210) population between groups on Day 56, using a Cochran-Mantel-Haenszel (CMH) test stratified by age (50-64 vs. ≥ 65 years). Only in presence of a significant overall effect, pair-wise comparisons between groups using CMH tests stratified by age was presented. As an overall test was produced before pair-wise comparisons were generated, no adjustment for multiple testing was performed.
    Comparison groups
    VLA84 200 μg w/o Alum v Placebo
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [6] - Inferential analysis; Only in presence of a significant overall effect, pair-wise comparisons between groups using CMH tests stratified by age was done. As an overall test was produced before pair-wise comparisons are generated, no adjustment for multiple testing was performed.
    Statistical analysis title
    		 comparison of SCR 200 w/ Alum vs. placebo
    Statistical analysis description
    The primary analysis compared the SCR against both Toxin A and Toxin B in the per-protocol (PP210) population between groups on Day 56, using a Cochran-Mantel-Haenszel (CMH) test stratified by age (50-64 vs. ≥ 65 years). Only in presence of a significant overall effect, pair-wise comparisons between groups using CMH tests stratified by age was presented. As an overall test was produced before pair-wise comparisons were generated, no adjustment for multiple testing was performed.
    Comparison groups
    Placebo v VLA84 200 μg w/ Alum
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [7] - Inferential analysis; Only in presence of a significant overall effect, pair-wise comparisons between groups using CMH tests stratified by age was done. As an overall test was produced before pair-wise comparisons are generated, no adjustment for multiple testing was performed.

    Secondary: Geometric Mean Titers (GMTs) for Toxin A- specific IgG antibodies (ELISA) on Day 56

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    End point title
    		 Geometric Mean Titers (GMTs) for Toxin A- specific IgG antibodies (ELISA) on Day 56
    End point description
    per-protocol population was primary analysis population (i.e., excluding subjects with major protocol deviations)
    End point type
    Secondary
    End point timeframe
    at Day 56
    End point values
    		 VLA84 75 µg w/o Alum VLA84 200 μg w/o Alum VLA84 200 μg w/ Alum Placebo
    Number of subjects analysed
    137
    135
    141
    46
    Units: EU/ml
        geometric mean (confidence interval 95%)
    2868.9 (2068.9 to 3978.1)
    4328.5 (3160.5 to 5928.3)
    4687.6 (3650.6 to 6019.3)
    33.9 (28.4 to 40.3)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers (GMTs) for Toxin B- specific IgG antibodies (ELISA) on Day 56

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    End point title
    		 Geometric Mean Titers (GMTs) for Toxin B- specific IgG antibodies (ELISA) on Day 56
    End point description
    per-protocol population was primary analysis population (i.e., excluding subjects with major protocol deviations)
    End point type
    Secondary
    End point timeframe
    on Day 56
    End point values
    		 VLA84 75 µg w/o Alum VLA84 200 μg w/o Alum VLA84 200 μg w/ Alum Placebo
    Number of subjects analysed
    137
    135
    141
    46
    Units: EU/ml
        geometric mean (confidence interval 95%)
    2370.5 (1641.2 to 3423.8)
    3336.5 (2398.9 to 4640.7)
    1449.4 (1001.8 to 2097.2)
    107.8 (77 to 151)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Event (AE) collection started at the time of first study vaccination. AEs were captured until the last study visit, i.e., Visit 8 (Day 210). Solicited local and systemic AEs were captured in a diary during 7 consecutive days after each vaccination
    Adverse event reporting additional description
    In addition memory aids were used for documentation of AEs up to Visit 6 (Day 56). Diary and memory aid were returned to and reviewed with site staff at the next visit. AEs beyond D56 were captured via interview of study participants during study visits.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    VLA84 75 mcg w/o Alum
    Reporting group description
    		 At each vaccination day (Day 0, 7 and 28) two injections were administered: 0.75 mL VLA84 w/o Alum and 0.75 mL Placebo

    Reporting group title
    VLA84 200 μg w/o Alum
    Reporting group description
    		 At each vaccination day (Day 0, 7 and 28) 2x 1.0 mL VLA84 w/o Alum (i.e. a total of 2 ml) were administered.

    Reporting group title
    VLA84 200 μg w/ Alum
    Reporting group description
    		 At each vaccination day (Day 0, 7 and 28) 2x 1.0 mL VLA84 w/ Alum (i.e. a total of 2 ml) were administered.

    Reporting group title
    Placebo
    Reporting group description
    		 At each vaccination day (Day 0, 7 and 28) 2x 1.0 mL placebo (i.e. a total of 2 ml) were administered.

    Serious adverse events
    		 VLA84 75 mcg w/o Alum VLA84 200 μg w/o Alum VLA84 200 μg w/ Alum Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 148 (2.70%)
    5 / 152 (3.29%)
    3 / 152 (1.97%)
    2 / 48 (4.17%)
         number of deaths (all causes)
    1
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial cancer
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 152 (0.00%)
    0 / 152 (0.00%)
    1 / 48 (2.08%)
         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
    Invasive ductal breast carcinoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 152 (0.66%)
    0 / 152 (0.00%)
    0 / 48 (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
    Investigations
    International normalised ratio increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 152 (0.00%)
    0 / 152 (0.00%)
    0 / 48 (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
    Injury, poisoning and procedural complications
    Incarcerated incisional hernia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 152 (0.00%)
    1 / 152 (0.66%)
    0 / 48 (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
    Tendon rupture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 152 (0.00%)
    0 / 152 (0.00%)
    0 / 48 (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
    Cardiac disorders
    Acute myocardial infarction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 152 (0.00%)
    1 / 152 (0.66%)
    0 / 48 (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
    Cardiac arrest
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 152 (0.00%)
    0 / 152 (0.00%)
    0 / 48 (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
    Cardiac failure congestive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 152 (0.00%)
    1 / 152 (0.66%)
    0 / 48 (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
    Surgical and medical procedures
    Inguinal hernia repair
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 152 (0.00%)
    0 / 152 (0.00%)
    1 / 48 (2.08%)
         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
    Nervous system disorders
    Cerebrovascular accident
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 152 (0.66%)
    0 / 152 (0.00%)
    0 / 48 (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
    General disorders and administration site conditions
    Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 152 (0.66%)
    0 / 152 (0.00%)
    0 / 48 (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
    Device dislocation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 152 (0.00%)
    0 / 152 (0.00%)
    0 / 48 (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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 152 (0.00%)
    0 / 152 (0.00%)
    0 / 48 (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
    Ileus
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 152 (0.00%)
    0 / 152 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 152 (0.00%)
    2 / 152 (1.32%)
    0 / 48 (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
    Chronic obstructive pulmonary disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 152 (0.66%)
    0 / 152 (0.00%)
    0 / 48 (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
    Psychiatric disorders
    Suicidal ideation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 152 (0.00%)
    0 / 152 (0.00%)
    0 / 48 (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
    Musculoskeletal and connective tissue disorders
    Spinal column stenosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 152 (0.00%)
    1 / 152 (0.66%)
    0 / 48 (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
    Infections and infestations
    Histoplasmosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 152 (0.00%)
    0 / 152 (0.00%)
    0 / 48 (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
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 152 (0.66%)
    0 / 152 (0.00%)
    0 / 48 (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
    Gangrene
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 152 (0.00%)
    1 / 152 (0.66%)
    0 / 48 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 VLA84 75 mcg w/o Alum VLA84 200 μg w/o Alum VLA84 200 μg w/ Alum Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    75 / 148 (50.68%)
    94 / 152 (61.84%)
    89 / 152 (58.55%)
    23 / 48 (47.92%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    36 / 148 (24.32%)
    31 / 152 (20.39%)
    36 / 152 (23.68%)
    13 / 48 (27.08%)
         occurrences all number
    49
    52
    49
    17
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    33 / 148 (22.30%)
    62 / 152 (40.79%)
    60 / 152 (39.47%)
    8 / 48 (16.67%)
         occurrences all number
    73
    137
    129
    21
    Fatigue
         subjects affected / exposed
    25 / 148 (16.89%)
    32 / 152 (21.05%)
    23 / 152 (15.13%)
    5 / 48 (10.42%)
         occurrences all number
    33
    41
    28
    9
    Influenza like illness
         subjects affected / exposed
    17 / 148 (11.49%)
    30 / 152 (19.74%)
    21 / 152 (13.82%)
    4 / 48 (8.33%)
         occurrences all number
    21
    38
    27
    6
    Injection site erythema
         subjects affected / exposed
    13 / 148 (8.78%)
    23 / 152 (15.13%)
    20 / 152 (13.16%)
    4 / 48 (8.33%)
         occurrences all number
    21
    33
    23
    4
    Injection site pruritus
         subjects affected / exposed
    9 / 148 (6.08%)
    18 / 152 (11.84%)
    15 / 152 (9.87%)
    1 / 48 (2.08%)
         occurrences all number
    12
    23
    17
    1
    Injection site swelling
         subjects affected / exposed
    7 / 148 (4.73%)
    14 / 152 (9.21%)
    17 / 152 (11.18%)
    2 / 48 (4.17%)
         occurrences all number
    8
    20
    20
    3
    Injection site induration
         subjects affected / exposed
    6 / 148 (4.05%)
    14 / 152 (9.21%)
    12 / 152 (7.89%)
    3 / 48 (6.25%)
         occurrences all number
    7
    17
    16
    5
    Pyrexia
         subjects affected / exposed
    4 / 148 (2.70%)
    9 / 152 (5.92%)
    3 / 152 (1.97%)
    0 / 48 (0.00%)
         occurrences all number
    4
    10
    4
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    16 / 148 (10.81%)
    12 / 152 (7.89%)
    14 / 152 (9.21%)
    6 / 48 (12.50%)
         occurrences all number
    20
    16
    18
    10
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 148 (6.08%)
    8 / 152 (5.26%)
    5 / 152 (3.29%)
    2 / 48 (4.17%)
         occurrences all number
    9
    10
    5
    3
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    17 / 148 (11.49%)
    29 / 152 (19.08%)
    25 / 152 (16.45%)
    6 / 48 (12.50%)
         occurrences all number
    23
    38
    29
    11
    Infections and infestations
    Sinusitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 148 (2.03%)
    1 / 152 (0.66%)
    0 / 152 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    3
    1
    0
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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