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    Clinical Trial Results:
    A randomized, placebo-controlled phase IIb (OEV 123) study to evaluate safety, immunogenicity, diagnostic methodology, and estimate vaccine efficacy of an oral enterotoxigenic Escherichia coli (ETEC) Vaccine (ETVAX) for prevention of clinically significant ETEC diarrhea in healthy adult travelers visiting West Africa

    Summary
    EudraCT number
    		 2016-002690-35
    Trial protocol
    		 FI  
    Global end of trial date
    15 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Dec 2021
    First version publication date
    13 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OEV 123
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03729219
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Scandinavian Biopharma Holding AB
    Sponsor organisation address
    Industrivägen 1, Solna, Sweden, 17148
    Public contact
    Björn Sjöstrand, CEO , Scandinavian Biopharma Holding AB , bjorn.sjostrand@scandinavianbiopharma.se
    Scientific contact
    Nils Carlin, VP Research and Development, Scandinavian Biopharma Holding AB , nils.carlin@etvax.se
    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
    27 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Safety: To evaluate safety and tolerability of orally administered ETVAX vaccine in a two-dose regimen Immunogenicity: To evaluate Immunoglobulin A (IgA) and Immunoglobulin G (IgG) antibody responses in serum against heat labile enterotoxin B (LTB). Diagnostic Tools: To elucidate the agreement between culture based and non-culture based diagnostic tools for identifying ETEC, and other enteric pathogens in stool samples from subjects meeting pre-defined clinical end-points for moderate or severe Traveler’s Diarrhea (TD). Culture-based diagnostics are performed on bacterial colonies isolated from stool samples and analyzed by biochemical, mass-spectrometric and immunological methods. Non-culture based methods are performed on frozen stool samples stored in eNAT tubes using a validated multiplex quantitative polymerase chain reaction (PCR) developed by Mobidiag Oy, Finland and a modified TaqMan array developed by University of Virginia (UVA) in the US.
    Protection of trial subjects
    In case of an emergency or when knowledge of the treatment assignment was absolutely necessary for the medical management of the study subject, the unblinding could be performed through electronic randomization system. Authorized investigators had 24/7 access to break the code per subject in case of an emergency. Reason, initials and date of opening the code was documented. The procedure of emergency unblinding was described in detail in Safety Management Plan (SMP).
    Background therapy
    		 All ongoing medication at the time of recruitment, including start/stop dates and indication, were recorded in the subject’s medical records as well as in the appropriate section of the eCRF. Atovaquone + proguanil (Malarone® / Rumbabor) was mandatory to take as prophylaxis for malaria. The intake of malaria prophylaxis was recorded in the subjects medical records and appropriate section of eCRF.
    Evidence for comparator
    		 Placebo used as comparator.
    Actual start date of recruitment
    31 May 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Finland: 782
    Worldwide total number of subjects
    782
    EEA total number of subjects
    782
    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)
    748
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study subjects were recruited among students, and personnel at the University of Helsinki and Helsinki University Hospital and among those responding to recruitment advertisements. To be eligible, the subjects had to commit to comply with the study protocol which involved vaccination, study visits, sampling and to travel to Benin.

    Pre-assignment
    Screening details
    		 Altogether, 8172 subjects contacted the study center and were prescreened over the phone. A total of 782 subjects were screened and 749 randomized into Group A and B equally, 374 in Active ETVAX group, 375 in placebo. In total, 729 subjects completed the study, and 20 discontinued during the trial. The total number of screening failures was 33.

    Pre-assignment period milestones
    Number of subjects started
    		 782
    Number of subjects completed
    		 749

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 29
    Reason: Number of subjects
    		 Protocol deviation: 4
    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, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ETVAX
    Arm description
    		 An ETEC vaccine which contains formaldehyde or phenol inactivated recombinant E. coli strains (ETEX 21-24) overexpressing colonization factors CFA/I, CS3, CS5, and CS6 and a recombinant protein LCTBA, a chimera between E. coli heat-labile enterotoxin B subunit (LTB) and Vibrio cholerae cholera toxin B-subunit (CTB) supplemented with an adjuvant, an inactivated double mutant LT(R192G/ L211A) of wild-type E. coli heat-labile toxin (dmLT), and an effervescent powder (bicarbonate buffer) mixed with 150 ml water
    Arm type
    		 Experimental

    Investigational medicinal product name
    ETVAX
    Investigational medicinal product code
    Other name
    ETEC vaccine
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Test product: Tetravalent ETEC vaccine with LCTBA supplemented with an adjuvant, double mutant heat labile toxin (dmLT), and an effervescent powder for oral solution (bicarbonate buffer). The ETEC vaccine (ETVAX) contains formaldehyde or phenol inactivated recombinant E. coli strains (ETEX 21-24) overexpressing colonization factors CFA/I, CS3, CS5, and CS6 and a recombinant protein LCTBA, a chimera between E. coli heat-labile enterotoxin B subunit (LTB) and Vibrio cholerae cholera toxin B-subunit (CTB). An adjuvant, an inactivated double mutant LT(R192G/ L211A) of wild-type E. coli heat-labile toxin (dmLT) is administered with the vaccine Dose: One dose contains in total approx. 8 x 10e10 inactivated bacteria and 1 mg of recombinant protein LCTBA in a 3.3 ml vial and 10 µg of adjuvant dmLT. All of these are mixed into 150 ml of effervescent bicarbonate buffer solution (5.6 g powder mixed with 150 ml water) to neutralize gastric acid upon ingestion. Two doses were given.

    Arm title
    		 Placebo
    Arm description
    		 Effervescent powder for oral solution (bicarbonate buffer) as control . Dose: 5.6 g/150 ml water
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Bicarbonate buffer
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Effervescent powder (bicarbonate buffer) in sachets. Dose: 5.6 g/150 ml water

    Number of subjects in period 1 [1]
    		ETVAX Placebo
    Started
    374
    375
    Completed
    363
    366
    Not completed
    11
    9
         Physician decision
    1
    -
         Consent withdrawn by subject
    3
    3
         Adverse event, non-fatal
    2
    1
         No reason recorded
    -
    1
         Lost to follow-up
    2
    2
         Protocol deviation
    3
    2
    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: Not all enrolled subject did not enter to vaccination i.e baseline period

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ETVAX
    Reporting group description
    		 An ETEC vaccine which contains formaldehyde or phenol inactivated recombinant E. coli strains (ETEX 21-24) overexpressing colonization factors CFA/I, CS3, CS5, and CS6 and a recombinant protein LCTBA, a chimera between E. coli heat-labile enterotoxin B subunit (LTB) and Vibrio cholerae cholera toxin B-subunit (CTB) supplemented with an adjuvant, an inactivated double mutant LT(R192G/ L211A) of wild-type E. coli heat-labile toxin (dmLT), and an effervescent powder (bicarbonate buffer) mixed with 150 ml water

    Reporting group title
    Placebo
    Reporting group description
    		 Effervescent powder for oral solution (bicarbonate buffer) as control . Dose: 5.6 g/150 ml water

    Reporting group values
    		 ETVAX Placebo Total
    Number of subjects
    		 374 375 749
    Age categorical
    Units: Subjects
        Adults(18-64 years)
    		 360 356 716
        From 65 to 85 years
    		 14 19 33
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.9 ( 15.5 ) 45.9 ( 15.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 260 269 529
        Male
    		 114 106 220
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects that received at least one dose of the vaccine or placebo.

    Subject analysis set title
    PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol population

    Subject analysis set title
    Post-hoc
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects having LTB IgA fold rise > 4 in active group

    Subject analysis set title
    Post hoc 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Post Hoc population 2 is a subset of the Per-Protocol Set (PPS) who experienced at least one Severe Traveler's diarrhea episode and in addition non-responders (i.e. less than 4-fold elevation in serum IgA antibody levels against LTB) were excluded from the analysis (apply to ETVAX group)

    Subject analysis sets values
    		 ITT PPS Post-hoc Post hoc 2
    Number of subjects
    749
    679
    599
    105
    Age categorical
    Units: Subjects
        Adults(18-64 years)
    716
    648
        From 65 to 85 years
    33
    31
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    46.4 ( 15.6 )
    46.4 ( 15.6 )
    47.5 ( 15.3 )
    46.1 ( 15.1 )
    Gender categorical
    Units: Subjects
        Female
    529
    479
    421
    74
        Male
    220
    200
    178
    31

    End points

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    End points reporting groups
    Reporting group title
    ETVAX
    Reporting group description
    		 An ETEC vaccine which contains formaldehyde or phenol inactivated recombinant E. coli strains (ETEX 21-24) overexpressing colonization factors CFA/I, CS3, CS5, and CS6 and a recombinant protein LCTBA, a chimera between E. coli heat-labile enterotoxin B subunit (LTB) and Vibrio cholerae cholera toxin B-subunit (CTB) supplemented with an adjuvant, an inactivated double mutant LT(R192G/ L211A) of wild-type E. coli heat-labile toxin (dmLT), and an effervescent powder (bicarbonate buffer) mixed with 150 ml water

    Reporting group title
    Placebo
    Reporting group description
    		 Effervescent powder for oral solution (bicarbonate buffer) as control . Dose: 5.6 g/150 ml water

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects that received at least one dose of the vaccine or placebo.

    Subject analysis set title
    PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol population

    Subject analysis set title
    Post-hoc
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects having LTB IgA fold rise > 4 in active group

    Subject analysis set title
    Post hoc 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Post Hoc population 2 is a subset of the Per-Protocol Set (PPS) who experienced at least one Severe Traveler's diarrhea episode and in addition non-responders (i.e. less than 4-fold elevation in serum IgA antibody levels against LTB) were excluded from the analysis (apply to ETVAX group)

    Primary: Number of Subjects Responding to Heat-labile Toxin (LTB) IgG

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    End point title
    		 Number of Subjects Responding to Heat-labile Toxin (LTB) IgG
    End point description
    The number of subjects having at least 2-fold rise of LTB specific IgG.
    End point type
    Primary
    End point timeframe
    Change from baseline (just before first vaccination) to Visit 3 (5-6 days after second vaccination), an average of 20 days
    End point values
    		 ETVAX Placebo ITT
    Number of subjects analysed
    370
    371
    741
    Units: Number of subjects
    270
    6
    276
    Statistical analysis title
    		 Number (%) Subjects with ≥ 2 Antibody fold rise
    Comparison groups
    ETVAX v Placebo
    Number of subjects included in analysis
    741
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Confidence interval

    Primary: Number of Subjects Responding to Heat-labile Toxin (LTB) IgA

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    End point title
    		 Number of Subjects Responding to Heat-labile Toxin (LTB) IgA
    End point description
    Number of subjects with at least 2-fold rise of LTB specific IgA.
    End point type
    Primary
    End point timeframe
    Change from baseline (just before first vaccination) to Visit 3 (5-6 days after second vaccination), an average of 20 days
    End point values
    		 ETVAX Placebo ITT
    Number of subjects analysed
    370
    372
    742
    Units: Number of subjects
    301
    8
    309
    Statistical analysis title
    		 Number (%) Subjects with ≥ 2 Antibody fold rise
    Comparison groups
    ETVAX v Placebo
    Number of subjects included in analysis
    742
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Incidence rate of moderate to severe travelers´ diarrhea (TD) caused by enterotoxigenic Escherichia coli expressing CFA/I, CS3, CS5 or CS6, and/or LT as single pathogen

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    End point title
    		 Incidence rate of moderate to severe travelers´ diarrhea (TD) caused by enterotoxigenic Escherichia coli expressing CFA/I, CS3, CS5 or CS6, and/or LT as single pathogen
    End point description
    Moderate Travelers´ diarrhea: 4-5 unformed/liquid stools in a 24-hour period associated with one or more of other symptoms as vomiting, fever, bloody stool, abdominal pain, cramping, nausea, lightheadedness, feeling weak and having an impact on daily activities. Severe Travelers´ diarrhea: ≥ 6 unformed/liquid stools in a 24-hour period associated with one or more of other symptoms and preventing planned daily activities. Stool sample containing an Enterotoxigenic Escherichia coli (ETEC) strain expressing CFA/I, CS3, CS5 or CS6, and/or LT as single pathogen (Vaccine Preventable Outcome), disregarding Enteropathogenic Escherichia coli (EPEC) and any other pathogens already present in at least one routine pre-travel stool sample.
    End point type
    Secondary
    End point timeframe
    Vaccination and surveillance period until return to home country and 30 day after return.
    End point values
    		 ETVAX Placebo PPS
    Number of subjects analysed
    333
    346
    679
    Units: Incidence of VPO
    26
    22
    48
    Statistical analysis title
    		 Protective efficacy
    Statistical analysis description
    Protective efficacy against first episode of specified type
    Comparison groups
    Placebo v ETVAX
    Number of subjects included in analysis
    679
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55
    Method
    		 Fisher exact
    Parameter type
    		 Protective efficacy
    Point estimate
    -23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -112
         upper limit
    		 29

    Post-hoc: Incidence rate of severe travelers' diarrhea (TD) all cause (responders)

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    End point title
    		 Incidence rate of severe travelers' diarrhea (TD) all cause (responders)
    End point description
    Severe Travelers´ diarrhea: ≥ 16 unformed/liquid stools in a 24-hour period associated with one or more of other symptoms as vomiting, fever, bloody stool, abdominal pain, cramping, nausea, lightheadedness, feeling weak and preventing planned daily activities. Stool sample containing any pathogen. The population analyzed was per protocol participants with responders to the vaccine defined as a 4-fold elevation in serum IgA antibody levels against LTB in active group.
    End point type
    Post-hoc
    End point timeframe
    Vaccination and surveillance period until return to home country and 30 days after return.
    End point values
    		 ETVAX Placebo Post-hoc
    Number of subjects analysed
    253
    346
    599
    Units: Number of subjects
        Yes
    10
    31
    41
        No
    243
    315
    558
    Statistical analysis title
    		 Protective efficacy
    Statistical analysis description
    Protective efficacy against first episode of specified type.
    Comparison groups
    ETVAX v Placebo v Post-hoc
    Number of subjects included in analysis
    1198
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.021
    Method
    		 Fisher exact
    Parameter type
    		 Protective efficacy
    Point estimate
    56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12
         upper limit
    		 78

    Post-hoc: Incidence rate of moderate to severe travelers´ diarrhea (TD) caused by enterotoxigenic Escherichia coli expressing CFA/I, CS3, CS5 or CS6, and/or LT confirmed in diarrhea and all other co-pathogens acceptable except viruses (responders)

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    End point title
    		 Incidence rate of moderate to severe travelers´ diarrhea (TD) caused by enterotoxigenic Escherichia coli expressing CFA/I, CS3, CS5 or CS6, and/or LT confirmed in diarrhea and all other co-pathogens acceptable except viruses (responders)
    End point description
    Moderate Travelers´ diarrhea: 4-5 unformed/liquid stools in a 24-hour period associated with one or more of other symptoms as vomiting, fever, bloody stool, abdominal pain, cramping, nausea, lightheadedness, feeling weak and having an impact on daily activities. Severe Travelers´ diarrhea: ≥ 6 unformed/liquid stools in a 24-hour period associated with one or more of other symptoms and preventing planned daily activities. Stool sample (confirmed diarrhea) containing an Enterotoxigenic Escherichia coli (ETEC) strain expressing CFA/I, CS3, CS5 or CS6, and/or LT and all other co-pathogens acceptable except viruses. The population analysed was per protocol participants with responders to the vaccine defined as a 4-fold elevation in serum IgA antibody levels against LTB in active group.
    End point type
    Post-hoc
    End point timeframe
    Vaccination and surveillance period until return to home country and 30 days after return.
    End point values
    		 ETVAX Placebo Post-hoc
    Number of subjects analysed
    253
    346
    599
    Units: Number of subjects
        Yes
    16
    46
    62
        No
    237
    300
    537
    Statistical analysis title
    		 Protective efficacy
    Comparison groups
    ETVAX v Placebo
    Number of subjects included in analysis
    599
    Analysis specification
    Post-hoc
    Analysis type
    P-value
    		 = 0.006
    Method
    		 Fisher exact
    Parameter type
    		 Protective efficacy
    Point estimate
    52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18
         upper limit
    		 72

    Post-hoc: Incidence rate of moderate to severe travelers' diarrhea (TD) caused by enterotoxigenic Escherichia coli expressing CFA/I, CS3, CS5 or CS6, and/or LT confirmed in diarrhea and all other co-pathogens acceptable except virus (regardless of immune response)

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    End point title
    		 Incidence rate of moderate to severe travelers' diarrhea (TD) caused by enterotoxigenic Escherichia coli expressing CFA/I, CS3, CS5 or CS6, and/or LT confirmed in diarrhea and all other co-pathogens acceptable except virus (regardless of immune response)
    End point description
    Moderate travelers´ diarrhea: 4-5 unformed/liquid stools in a 24-hour period associated with one or more of other symptoms as vomiting, fever, bloody stool, abdominal pain, cramping, nausea, lightheadedness, feeling weak and having an impact on daily activities. Severe Travelers´ diarrhea: ≥ 6 unformed/liquid stools in a 24-hour period associated with one or more of other symptoms and preventing planned daily activities. Stool sample (confirmed diarrhea) containing an Enterotoxigenic Escherichia coli (ETEC) strain expressing CFA/I, CS3, CS5 or CS6, and/or LT and all other co-pathogens acceptable except viruses.
    End point type
    Post-hoc
    End point timeframe
    Vaccination and surveillance period until return to home country and 30 days after return.
    End point values
    		 ETVAX Placebo PPS
    Number of subjects analysed
    333
    346
    679
    Units: Number of subjects
    26
    46
    72
    Statistical analysis title
    		 Protective efficacy
    Comparison groups
    ETVAX v Placebo
    Number of subjects included in analysis
    679
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 Fisher exact
    Parameter type
    		 Protective efficacy
    Point estimate
    41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7
         upper limit
    		 63

    Post-hoc: Incidence rate of severe travelers´ diarrhea (TD) all cause (regardless of immune response)

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    End point title
    		 Incidence rate of severe travelers´ diarrhea (TD) all cause (regardless of immune response)
    End point description
    Severe Travelers´ diarrhea: ≥ 16 unformed/liquid stools in a 24-hour period associated with one or more of other symptoms as vomiting, fever, bloody stool, abdominal pain, cramping, nausea, lightheadedness, feeling weak and preventing planned daily activities. Stool sample containing any pathogen. Regardless of immune response
    End point type
    Post-hoc
    End point timeframe
    Vaccination and surveillance period until return to home country and 30 days after return.
    End point values
    		 ETVAX Placebo PPS
    Number of subjects analysed
    333
    346
    679
    Units: Number of subjects
    17
    31
    48
    Statistical analysis title
    		 Protective efficacy
    Comparison groups
    ETVAX v Placebo
    Number of subjects included in analysis
    679
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.053
    Method
    		 Fisher exact
    Parameter type
    		 Protective efficacy
    Point estimate
    43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 68

    Post-hoc: Proportion of subjects who used anti-diarrheal medications or antibiotics during Severe Traveler's diarrhea episode

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    End point title
    		 Proportion of subjects who used anti-diarrheal medications or antibiotics during Severe Traveler's diarrhea episode
    End point description
    The population analysed was the Post Hoc population 2 (subset of the Per-Protocol Set (PPS) who experienced at least one Severe Traveler's diarrhea episode, non-responders (i.e. less than 4-fold elevation in serum IgA antibody levels against LTB) were excluded (apply to ETVAX group). Severe Travelers´ diarrhea as defined as follows : ≥ 6 unformed/liquid stools in a 24-hour period associated with one or more of other symptoms and preventing planned daily activities. Antibiotics were specified by ATC codes J01 and J04, and anti-diarrheal medications by ATC codes A07B, A07C, A07D, A07F, and A07X.
    End point type
    Post-hoc
    End point timeframe
    Vaccination and surveillance period until return to home country and 30 days after return.
    End point values
    		 ETVAX Placebo Post hoc 2
    Number of subjects analysed
    44
    61
    105
    Units: Number of subjects
        No medication
    28
    24
    52
        Medication
    16
    37
    53
    Statistical analysis title
    		 Proportion of subjects
    Statistical analysis description
    Proportion of subjects who used anti-diarrheal medications or antibiotics during Severe TD
    Comparison groups
    ETVAX v Placebo
    Number of subjects included in analysis
    105
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.018
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.374
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.154
         upper limit
    		 0.887

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse event reporting period for this study began after receiving the first dose of IMP and ended the day the subject travelled to Benin or at the withdrawal of the subject. On-going AEs at the end of the study period were followed until resolution.
    Adverse event reporting additional description
    AEs and SAEs reported here were collected also during the surveillance period. None of the SAEs were not reported during the vaccine attributable period , but thereafter.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    ETVAX
    Reporting group description
    		 The adverse event reporting period for this study began after receiving the first dose of IMP and ended the day the subject travelled to Benin or at the withdrawal of the subject. On-going AEs at the end of the study period were followed until resolution or until the whole follow-up period back in Finland (30 days), whichever came first.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 ETVAX Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 374 (4.55%)
    24 / 375 (6.40%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Joint dislocation
         subjects affected / exposed
    1 / 374 (0.27%)
    0 / 375 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 374 (0.00%)
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 374 (0.27%)
    0 / 375 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 374 (0.00%)
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 374 (0.27%)
    4 / 375 (1.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 374 (0.00%)
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 374 (0.27%)
    0 / 375 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 374 (0.00%)
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 374 (0.27%)
    0 / 375 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    4 / 374 (1.07%)
    4 / 375 (1.07%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 374 (0.27%)
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    3 / 374 (0.80%)
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 374 (0.00%)
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 374 (0.53%)
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 374 (0.27%)
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonella sepsis
         subjects affected / exposed
    1 / 374 (0.27%)
    3 / 375 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingitis
         subjects affected / exposed
    0 / 374 (0.00%)
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shigella infection
         subjects affected / exposed
    0 / 374 (0.00%)
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 374 (0.00%)
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 374 (0.00%)
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 ETVAX Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    289 / 374 (77.27%)
    284 / 375 (75.73%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    13 / 374 (3.48%)
    10 / 375 (2.67%)
         occurrences all number
    17
    12
    Headache
         subjects affected / exposed
    71 / 374 (18.98%)
    87 / 375 (23.20%)
         occurrences all number
    96
    126
    Migraine
         subjects affected / exposed
    6 / 374 (1.60%)
    10 / 375 (2.67%)
         occurrences all number
    8
    15
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    25 / 374 (6.68%)
    21 / 375 (5.60%)
         occurrences all number
    25
    23
    Pyrexia
         subjects affected / exposed
    22 / 374 (5.88%)
    22 / 375 (5.87%)
         occurrences all number
    24
    24
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    7 / 374 (1.87%)
    2 / 375 (0.53%)
         occurrences all number
    9
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    9 / 374 (2.41%)
    7 / 375 (1.87%)
         occurrences all number
    11
    10
    Abdominal distension
         subjects affected / exposed
    6 / 374 (1.60%)
    7 / 375 (1.87%)
         occurrences all number
    9
    7
    Abdominal pain upper
         subjects affected / exposed
    90 / 374 (24.06%)
    77 / 375 (20.53%)
         occurrences all number
    122
    109
    Constipation
         subjects affected / exposed
    5 / 374 (1.34%)
    6 / 375 (1.60%)
         occurrences all number
    6
    8
    Diarrhoea
         subjects affected / exposed
    109 / 374 (29.14%)
    103 / 375 (27.47%)
         occurrences all number
    150
    150
    Dyspepsia
         subjects affected / exposed
    8 / 374 (2.14%)
    9 / 375 (2.40%)
         occurrences all number
    11
    10
    Eructation
         subjects affected / exposed
    11 / 374 (2.94%)
    9 / 375 (2.40%)
         occurrences all number
    13
    12
    Flatulence
         subjects affected / exposed
    26 / 374 (6.95%)
    18 / 375 (4.80%)
         occurrences all number
    32
    25
    Nausea
         subjects affected / exposed
    80 / 374 (21.39%)
    66 / 375 (17.60%)
         occurrences all number
    110
    86
    Vomiting
         subjects affected / exposed
    16 / 374 (4.28%)
    9 / 375 (2.40%)
         occurrences all number
    18
    9
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    7 / 374 (1.87%)
    10 / 375 (2.67%)
         occurrences all number
    9
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 374 (2.94%)
    7 / 375 (1.87%)
         occurrences all number
    11
    7
    Nasal congestion
         subjects affected / exposed
    4 / 374 (1.07%)
    9 / 375 (2.40%)
         occurrences all number
    4
    9
    Oropharyngeal pain
         subjects affected / exposed
    21 / 374 (5.61%)
    24 / 375 (6.40%)
         occurrences all number
    22
    24
    Rhinorrhoea
         subjects affected / exposed
    15 / 374 (4.01%)
    12 / 375 (3.20%)
         occurrences all number
    16
    12
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    5 / 374 (1.34%)
    5 / 375 (1.33%)
         occurrences all number
    5
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    16 / 374 (4.28%)
    9 / 375 (2.40%)
         occurrences all number
    16
    18
    Back pain
         subjects affected / exposed
    16 / 374 (4.28%)
    10 / 375 (2.67%)
         occurrences all number
    16
    13
    Musculoskeletal pain
         subjects affected / exposed
    6 / 374 (1.60%)
    5 / 375 (1.33%)
         occurrences all number
    6
    7
    Myalgia
         subjects affected / exposed
    15 / 374 (4.01%)
    7 / 375 (1.87%)
         occurrences all number
    21
    8
    Neck pain
         subjects affected / exposed
    2 / 374 (0.53%)
    7 / 375 (1.87%)
         occurrences all number
    2
    8
    Pain in extremity
         subjects affected / exposed
    7 / 374 (1.87%)
    5 / 375 (1.33%)
         occurrences all number
    8
    5
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    4 / 374 (1.07%)
    4 / 375 (1.07%)
         occurrences all number
    4
    4
    Influenza
         subjects affected / exposed
    30 / 374 (8.02%)
    21 / 375 (5.60%)
         occurrences all number
    32
    24
    Nasopharyngitis
         subjects affected / exposed
    12 / 374 (3.21%)
    11 / 375 (2.93%)
         occurrences all number
    12
    11

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Apr 2017
    Amendment 1; Protocol Version 2.0 and respective updates of ICF
    22 May 2017
    Amendment 2; Protocol version 3.0 and respective updates of ICFs
    24 Jul 2017
    Amendment 3; Protocol Version 4.1 and respective updates of ICF and approval for subject questionnaires
    18 Sep 2017
    Amendment 4; protocol version 5.0 and respective updates in ICF and subject materials
    23 May 2018
    Amendment 5; Protocol version 6.0 and respective updates in ICF and study documents

    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
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