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    Clinical Trial Results:
    A Phase 4 Study to Assess the Safety and Immunogenicity of VAXCHORA (Cholera Vaccine, Live, Oral) in Children 2 to <18 Years of Age

    Summary
    EudraCT number
    		 2018-003850-25
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    10 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jul 2020
    First version publication date
    15 Jul 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PXVX-VC-200-006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03220737
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Emergent Travel Health Inc.
    Sponsor organisation address
    555 Twin Dolphin Drive, Suite 360 , Redwood City, California, United States, 94065
    Public contact
    David Cassie Scientist, Clinical Research, Emergent Travel Health Inc., +1 2042754589, dcassie@ebsi.com
    Scientific contact
    David Cassie Scientist, Clinical Research, Emergent Travel Health Inc., +1 2042754589, dcassie@ebsi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001490-PIP01-13
    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
    06 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1) For each of Cohort 1: 12 to <18 years, Cohort 2: 6 to <12 years and Cohort 3: 2 to <6 years Primary Immunogenicity Objectives: • Demonstrate that the seroconversion rate at Day 11 in pediatric subjects is non-inferior to the seroconversion rate at Day 11 in adults between the ages of 18 and 45 years. • Demonstrate that the seroconversion rate in pediatric subjects is greater than or equal to 70% with 98.3% confidence. Primary Safety Objectives: Objective: • Evaluate the safety and clinical acceptability of Vaxchora vaccine in children. • Evaluate the acceptability of Vaxchora vaccine • Evaluate the palatability of Vaxchora vaccine
    Protection of trial subjects
    Prior to any study related activities, the subjects’ parent or legal guardian signed and dated an Institutional Review Board (IRB) approved informed consent form (ICF). Subjects within the older cohort 1 provided written assent. This study was conducted in accordance with the clinical research guidelines established by the Basic Principles defined in the U.S. 21 CFR Part 50, 54, 56 and 312 (for studies conducted in the U.S. only), the principles enunciated in the latest version of The Declaration of Helsinki and the International Conference on Harmonization (ICH) Harmonized Tripartite Guideline for Good Clinical Practice (GCP) (ICH E6).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Jul 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 3238
    Worldwide total number of subjects
    3238
    EEA total number of subjects
    0
    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)
    361
    Adolescents (12-17 years)
    189
    Adults (18-64 years)
    2688
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This study included healthy volunteers (2 - 17 years) who were not previously immunized against cholera. A total of 574 subjects were screened, of which 24 were screen failures. A total of 550 subjects randomized, of which 471 received study treatment and 433 and 62 completed the main and sub studies, respectively. Recruitment July 2017-July 2018.

    Pre-assignment
    Screening details
    		 This study included healthy volunteers (2 - 17 years) who were not previously immunized against cholera. A total of 574 subjects were screened, of which 24 were screen failures. A total of 550 subjects randomized, of which 471 received study treatment and 433 and 62 completed the main and sub studies, respectively. Recruitment July 2017-July 2018.

    Period 1
    Period 1 title
    Main Study (Day 1 - 181)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 (active, 12-17 yrs)
    Arm description
    		 Subjects aged 12 - 17 were administered a 100 mL oral dose of Vaxchora vaccine on Day 1, and had study visits on Day 11, 29, 91 and 181.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vaxchora (Cholera Vaccine, live attenuated, oral)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The buffer component was dissolved in 100 mL of cold or room temperature bottled water. The active component (lyophilized V. cholerae CVD 103-HgR) was then added into the buffer solution. Mixture was stirred until a cloudy suspension was achieved. Stevia was added at the discretion of the HCP and the subject consumed the dose within 15 mins of preparation. Only one dose (1 x 10e9 cfu/dose) was administered in this study.

    Arm title
    		 Cohort 1 (placebo, 12-17 yrs)
    Arm description
    		 Subjects aged 12 - 17 were administered a 100 mL oral dose of placebo on Day 1, and had study visits on Day 11, 29, 91 and 181.
    Arm type
    		 Placebo

    Investigational medicinal product name
    0.9% Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    100 mL of cold or room temperature 0.9% saline was dispensed. Stevia was added at the discretion of the HCP and the subject consumed the dose within 15 mins of preparation. Only one dose was administered in this study.

    Arm title
    		 Cohort 2 (active, 6-11 yrs)
    Arm description
    		 Subjects aged 6 - 11 were administered a 100 mL oral dose of Vaxchora vaccine on Day 1, and had study visits on Day 11, 29, 91 and 181.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vaxchora (Cholera Vaccine, live attenuated, oral)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The buffer component was dissolved in 100 mL of cold or room temperature bottled water. The active component (lyophilized V. cholerae CVD 103-HgR) was then added into the buffer solution. Mixture was stirred until a cloudy suspension was achieved. Stevia was added at the discretion of the HCP and the subject consumed the dose within 15 mins of preparation. Only one dose (1 x 10e9 cfu/dose) was administered in this study.

    Arm title
    		 Cohort 2 (placebo, 6-11 yrs)
    Arm description
    		 Subjects aged 6 - 11 were administered a 100 mL oral dose of placebo on Day 1, and had study visits on Day 11, 29, 91 and 181.
    Arm type
    		 Placebo

    Investigational medicinal product name
    0.9% Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    100 mL of cold or room temperature 0.9% saline was dispensed. Stevia was added at the discretion of the HCP and the subject consumed the dose within 15 mins of preparation. Only one dose was administered in this study.

    Arm title
    		 Cohort 3 (active, 2-5 yrs)
    Arm description
    		 Subjects aged 2 - 5 were administered a 50 mL oral dose of Vaxchora vaccine on Day 1, and had study visits on Day 11, 29, 91 and 181
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vaxchora (Cholera Vaccine, live attenuated, oral)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The buffer component was dissolved in 100 mL of cold or room temperature bottled water. After buffer was dissolved 50mL was discarded. The active component (lyophilized V. cholerae CVD 103-HgR) was then added into the 50 mL buffer solution. Mixture was stirred until a cloudy suspension was achieved. Stevia was added at the discretion of the HCP and the subject consumed the dose within 15 mins of preparation. Only one dose (1 x 10e9 cfu/dose) was administered in this study.

    Arm title
    		 Cohort 3 (placebo, 2-5 yrs)
    Arm description
    		 Subjects aged 2 - 5 were administered a 50 mL oral dose of placebo on Day 1, and had study visits on Day 11, 29, 91 and 181.
    Arm type
    		 Placebo

    Investigational medicinal product name
    0.9% Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    50 mL of cold or room temperature 0.9% saline was dispensed. Stevia was added at the discretion of the HCP and the subject consumed the dose within 15 mins of preparation. Only one dose was administered in this study.

    Arm title
    		 Adult bridging population
    Arm description
    		 This arm consists of historical data from Vaxchora vaccine subjects from study PXVX-VC-200-004. The data was included in study PXVX-VC-200-006 as a comparator bridging population for the Day 11 seroconversion.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vaxchora (Cholera Vaccine, live attenuated, oral)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The buffer component was dissolved in 100 mL of cold or room temperature bottled water. The active component (lyophilized V. cholerae CVD 103-HgR) was then added into the buffer solution. Mixture was stirred until a cloudy suspension was achieved. Stevia was added at the discretion of the HCP and the subject consumed the dose within 15 mins of preparation. Only one dose (1 x 109 cfu/dose) was administered in this study.

    Number of subjects in period 1
    		Cohort 1 (active, 12-17 yrs) Cohort 1 (placebo, 12-17 yrs) Cohort 2 (active, 6-11 yrs) Cohort 2 (placebo, 6-11 yrs) Cohort 3 (active, 2-5 yrs) Cohort 3 (placebo, 2-5 yrs) Adult bridging population
    Started
    163
    26
    158
    27
    150
    26
    2688
    Day 11
    162
    26
    155
    26
    144
    25
    2687
    Day 29
    161
    26
    154
    26
    141
    25
    2687
    Day 91
    160
    26
    153
    26
    139
    25
    2687
    Day 181
    157
    24
    146
    24
    130
    25
    2687
    Completed
    157
    24
    146
    24
    130
    25
    2687
    Not completed
    6
    2
    12
    3
    20
    1
    1
         Consent withdrawn by subject
    4
    1
    4
    1
    4
    -
    -
         Failed Exl 8 and randomized in error
    -
    -
    1
    -
    -
    -
    -
         Lost to follow-up
    2
    1
    6
    1
    13
    1
    -
         Protocol deviation
    -
    -
    1
    1
    3
    -
    1
    Period 2
    Period 2 title
    Long-term Sub-study (Day 181 - 730)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer

    Arms
    Arm title
    		 Cohort 1 Long-term (active, 12-17 yrs)
    Arm description
    		 Subjects aged 12 - 17 from the main study treatment arm had additional study visits on Day 365, 547 and 730.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vaxchora (Cholera Vaccine, live attenuated, oral)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The buffer component was dissolved in 100 mL of cold or room temperature bottled water. The active component (lyophilized V. cholerae CVD 103-HgR) was then added into the buffer solution. Mixture was stirred until a cloudy suspension was achieved. Stevia was added at the discretion of the HCP and the subject consumed the dose within 15 mins of preparation. Only one dose (1 x 10e9 cfu/dose) was administered in this study.

    Number of subjects in period 2 [1]
    		Cohort 1 Long-term (active, 12-17 yrs)
    Started
    73
    Day 365
    71
    Day 547
    68
    Completed
    62
    Not completed
    11
         Consent withdrawn by subject
    1
         Subject chose to drop due to not wanting lab drawn
    1
         Lost to follow-up
    9
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The long-term sub-study was optional for Cohort 1 subjects in the main study. A total of 73 subjects opted to continue with SVA assessments out to Day 730.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 (active, 12-17 yrs)
    Reporting group description
    		 Subjects aged 12 - 17 were administered a 100 mL oral dose of Vaxchora vaccine on Day 1, and had study visits on Day 11, 29, 91 and 181.

    Reporting group title
    Cohort 1 (placebo, 12-17 yrs)
    Reporting group description
    		 Subjects aged 12 - 17 were administered a 100 mL oral dose of placebo on Day 1, and had study visits on Day 11, 29, 91 and 181.

    Reporting group title
    Cohort 2 (active, 6-11 yrs)
    Reporting group description
    		 Subjects aged 6 - 11 were administered a 100 mL oral dose of Vaxchora vaccine on Day 1, and had study visits on Day 11, 29, 91 and 181.

    Reporting group title
    Cohort 2 (placebo, 6-11 yrs)
    Reporting group description
    		 Subjects aged 6 - 11 were administered a 100 mL oral dose of placebo on Day 1, and had study visits on Day 11, 29, 91 and 181.

    Reporting group title
    Cohort 3 (active, 2-5 yrs)
    Reporting group description
    		 Subjects aged 2 - 5 were administered a 50 mL oral dose of Vaxchora vaccine on Day 1, and had study visits on Day 11, 29, 91 and 181

    Reporting group title
    Cohort 3 (placebo, 2-5 yrs)
    Reporting group description
    		 Subjects aged 2 - 5 were administered a 50 mL oral dose of placebo on Day 1, and had study visits on Day 11, 29, 91 and 181.

    Reporting group title
    Adult bridging population
    Reporting group description
    		 This arm consists of historical data from Vaxchora vaccine subjects from study PXVX-VC-200-004. The data was included in study PXVX-VC-200-006 as a comparator bridging population for the Day 11 seroconversion.

    Reporting group values
    		 Cohort 1 (active, 12-17 yrs) Cohort 1 (placebo, 12-17 yrs) Cohort 2 (active, 6-11 yrs) Cohort 2 (placebo, 6-11 yrs) Cohort 3 (active, 2-5 yrs) Cohort 3 (placebo, 2-5 yrs) Adult bridging population Total
    Number of subjects
    		 163 26 158 27 150 26 2688 3238
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 158 27 150 26 0 361
        Adolescents (12-17 years)
    		 163 26 0 0 0 0 0 189
        Adults (18-64 years)
    		 0 0 0 0 0 0 2688 2688
        From 65-84 years
    		 0 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.4 ( 1.7 ) 14.3 ( 1.7 ) 8.6 ( 1.8 ) 8.7 ( 1.5 ) 3.5 ( 1.1 ) 3.6 ( 1.2 ) 30.0 ( 7.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 75 12 81 10 69 17 1482 1746
        Male
    		 88 14 77 17 81 9 1206 1492
    Race
    Units: Subjects
        White
    		 121 21 86 18 71 12 1855 2184
        Black or African American
    		 28 4 53 5 67 14 671 842
        Multiple
    		 13 0 15 3 11 0 50 92
        American Indian or Alaska Native
    		 0 1 0 1 1 0 11 14
        Asian
    		 1 0 4 0 0 0 56 61
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 8 8
        Other
    		 0 0 0 0 0 0 37 37
    Subject analysis sets

    Subject analysis set title
    Randomized Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This population includes all subjects randomized into the study.

    Subject analysis set title
    All Ages Immunogenicity Evaluable Population (IEP)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects who received the study treatment, had serum titers for both Day 1 and Day 11, and had no other major deviations which could potentially affect immunogenicity

    Subject analysis set title
    Adult Bridging Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The historical data from Vaxchora vaccine subjects in study PXVX-VX-200-004 was included as a comparator bridging population for the Day 11 seroconversion in paediatrics. The IEP population was 2688 subjects and there were 2687 for the Day 11 comparison.

    Subject analysis sets values
    		 Randomized Population All Ages Immunogenicity Evaluable Population (IEP) Adult Bridging Population
    Number of subjects
    550
    399
    2688
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    361
    0
    0
        Adolescents (12-17 years)
    189
    0
    0
        Adults (18-64 years)
    0
    0
    2688
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    9.0 ( 4.7 )
    9.6 ( 4.6 )
    30.0 ( 7.8 )
    Gender categorical
    Units: Subjects
        Female
    264
    188
    1482
        Male
    286
    211
    1206
    Race
    Units: Subjects
        White
    329
    238
    1855
        Black or African American
    171
    123
    671
        Multiple
    42
    33
    50
        American Indian or Alaska Native
    5
    1
    11
        Asian
    3
    4
    56
        Native Hawaiian or Other Pacific Islander
    0
    0
    8
        Other
    0
    0
    37

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 (active, 12-17 yrs)
    Reporting group description
    		 Subjects aged 12 - 17 were administered a 100 mL oral dose of Vaxchora vaccine on Day 1, and had study visits on Day 11, 29, 91 and 181.

    Reporting group title
    Cohort 1 (placebo, 12-17 yrs)
    Reporting group description
    		 Subjects aged 12 - 17 were administered a 100 mL oral dose of placebo on Day 1, and had study visits on Day 11, 29, 91 and 181.

    Reporting group title
    Cohort 2 (active, 6-11 yrs)
    Reporting group description
    		 Subjects aged 6 - 11 were administered a 100 mL oral dose of Vaxchora vaccine on Day 1, and had study visits on Day 11, 29, 91 and 181.

    Reporting group title
    Cohort 2 (placebo, 6-11 yrs)
    Reporting group description
    		 Subjects aged 6 - 11 were administered a 100 mL oral dose of placebo on Day 1, and had study visits on Day 11, 29, 91 and 181.

    Reporting group title
    Cohort 3 (active, 2-5 yrs)
    Reporting group description
    		 Subjects aged 2 - 5 were administered a 50 mL oral dose of Vaxchora vaccine on Day 1, and had study visits on Day 11, 29, 91 and 181

    Reporting group title
    Cohort 3 (placebo, 2-5 yrs)
    Reporting group description
    		 Subjects aged 2 - 5 were administered a 50 mL oral dose of placebo on Day 1, and had study visits on Day 11, 29, 91 and 181.

    Reporting group title
    Adult bridging population
    Reporting group description
    		 This arm consists of historical data from Vaxchora vaccine subjects from study PXVX-VC-200-004. The data was included in study PXVX-VC-200-006 as a comparator bridging population for the Day 11 seroconversion.
    Reporting group title
    Cohort 1 Long-term (active, 12-17 yrs)
    Reporting group description
    		 Subjects aged 12 - 17 from the main study treatment arm had additional study visits on Day 365, 547 and 730.

    Subject analysis set title
    Randomized Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This population includes all subjects randomized into the study.

    Subject analysis set title
    All Ages Immunogenicity Evaluable Population (IEP)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects who received the study treatment, had serum titers for both Day 1 and Day 11, and had no other major deviations which could potentially affect immunogenicity

    Subject analysis set title
    Adult Bridging Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The historical data from Vaxchora vaccine subjects in study PXVX-VX-200-004 was included as a comparator bridging population for the Day 11 seroconversion in paediatrics. The IEP population was 2688 subjects and there were 2687 for the Day 11 comparison.

    Primary: Seroconversion rate at Day 11 in paediatric subjects

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    End point title
    		 Seroconversion rate at Day 11 in paediatric subjects [1]
    End point description
    The seroconversion rate was defined as the percentage of subjects with a 4-fold or greater rise from Day 1 in Serum Vibriocidal Antibody titers (SVA) against the classical Inaba biotype of V. cholerae at Day 11 following one dose of Vaxchora vaccine. The objective was to demonstrate that the seroconversion rate at Day 11 in paediatric subjects is greater than or equal to 70% with 98.3% confidence.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 11
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is for seroconversion in paedatric subjects only. The adult bridging population, which is historical data, is included as an arm for a comparator only for the subsequent primary endpoint.
    End point values
    		 Cohort 1 (active, 12-17 yrs) Cohort 1 (placebo, 12-17 yrs) Cohort 2 (active, 6-11 yrs) Cohort 2 (placebo, 6-11 yrs) Cohort 3 (active, 2-5 yrs) Cohort 3 (placebo, 2-5 yrs) All Ages Immunogenicity Evaluable Population (IEP)
    Number of subjects analysed
    157
    23
    139
    24
    103
    20
    399
    Units: % of participants
    number (confidence interval 98.3%)
        % Seroconverted at Day 11
    99.4 (95.4 to 99.9)
    0 (0.0 to 14.3)
    97.8 (92.5 to 99.4)
    4.2 (0.7 to 20.2)
    98.1 (91.5 to 99.6)
    0 (0.0 to 16.1)
    98.5 (96.2 to 99.4)
    Statistical analysis title
    		 Proportion of subjects seroconverted at Day 11
    Statistical analysis description
    This analysis was based on the lower confidence limit and did not entail a comparative group. The requirement was for the lower limit of the 98.3% CI be at least 70%. Multiplicity adjustment due to co-primary endpoints allotted alpha=0.017 to this endpoint resulting in a 98.3% confidence interval
    Comparison groups
    Cohort 2 (active, 6-11 yrs) v Cohort 3 (active, 2-5 yrs) v Cohort 1 (active, 12-17 yrs)
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 proportion
    Point estimate
    98.5
    Confidence interval
         level
    		 98.3%
         sides
    1-sided
         lower limit
    		 0.7
         upper limit
    		 -
    Notes
    [2] - This analysis was based on the lower confidence limit and did not entail a comparative group. The requirement was for the lower limit of the 98.3% CI be at least 70%. Multiplicity adjustment due to co-primary endpoints allotted alpha=0.017 to this endpoint resulting in a 98.3% confidence interval

    Primary: Non-inferiority of seroconversion rate at Day 11 in Cohort 1 (12-17 yrs) subjects relative to adult subjects aged 18 - 45 years

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    End point title
    		 Non-inferiority of seroconversion rate at Day 11 in Cohort 1 (12-17 yrs) subjects relative to adult subjects aged 18 - 45 years [3]
    End point description
    The seroconversion rate is defined as the percentage of subjects with a 4-fold or greater rise over baseline Day 1 Serum Vibriocidal Antibody (SVA) titer against the classical Inaba biotype of V. cholerae at Day 11 following one dose of Vaxchora vaccine. The objective was to demonstrate that the paediatric seroconversion rate is non-inferior to the seroconversion rate at Day 11 in adults between the ages of 18 and 45 years.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 11
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is a comparison of solely cohort 1 and the adult bridging population. Cohorts 2 and 3 are presented seperately. The placebo groups for all cohorts was not included in this non-inferiority analysis.
    End point values
    		 Cohort 1 (active, 12-17 yrs) Adult bridging population
    Number of subjects analysed
    157
    2687
    Units: % of participants
        number (confidence interval 98.3%)
    99.4 (95.4 to 99.9)
    93.5 (92.3 to 94.6)
    Statistical analysis title
    		 Difference in % Seroconversion at Day 11, Cohort 1
    Statistical analysis description
    Non-inferiority was determined using the Newcombe method of determining the difference between two independent binomial distributions. Multiple comparison adjustment for co-primary endpoints allotted alpha=0.033 to this comparison. The lower limit of the 96.7% CI needed to be greater than -10 percentage points to prove non-inferiority
    Comparison groups
    Cohort 1 (active, 12-17 yrs) v Adult bridging population
    Number of subjects included in analysis
    2844
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    		 Newcombe
    Parameter type
    		 Risk difference (RD)
    Point estimate
    5.8
    Confidence interval
         level
    		 96.7%
         sides
    2-sided
         lower limit
    		 2.4
         upper limit
    		 7.1
    Notes
    [4] - Newcombe method of determining the difference between two independent binomial distributions

    Primary: Non-inferiority of seroconversion rate at Day 11 in Cohort 2 (6-11 yrs) subjects relative to adult subjects aged 18 - 45 years

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    End point title
    		 Non-inferiority of seroconversion rate at Day 11 in Cohort 2 (6-11 yrs) subjects relative to adult subjects aged 18 - 45 years [5]
    End point description
    The seroconversion rate is defined as the percentage of subjects with a 4-fold or greater rise over baseline Day 1 Serum Vibriocidal Antibody (SVA) titer against the classical Inaba biotype of V. cholerae at Day 11 following one dose of Vaxchora vaccine. The objective was to demonstrate that the paediatric seroconversion rate is non-inferior to the seroconversion rate at Day 11 in adults between the ages of 18 and 45 years.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 11
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is a comparison of solely cohort 2 and the adult bridging population. Cohorts 1 and 3 are presented seperately. The placebo groups for all cohorts was not included in this non-inferiority analysis.
    End point values
    		 Cohort 2 (active, 6-11 yrs) Adult bridging population
    Number of subjects analysed
    139
    2687
    Units: % of participants
    number (confidence interval 98.3%)
        % seroconverted
    97.8 (92.5 to 99.4)
    93.5 (92.3 to 94.6)
    Statistical analysis title
    		 Difference in % Seroconversion at Day 11, Cohort 2
    Statistical analysis description
    Non-inferiority was determined using the Newcombe method of determining the difference between two independent binomial distributions. Multiple comparison adjustment for co-primary endpoints allotted alpha=0.033 to this comparison. The lower limit of the 96.7% CI needed to be greater than -10 percentage points to prove non-inferiority
    Comparison groups
    Adult bridging population v Cohort 2 (active, 6-11 yrs)
    Number of subjects included in analysis
    2826
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    4.3
    Confidence interval
         level
    		 96.7%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 6.2
    Notes
    [6] - Newcombe method of determining the difference between two independent binomial distributions

    Primary: Non-inferiority of seroconversion rate at Day 11 in Cohort 3 (2-5 yrs) subjects relative to adult subjects aged 18 - 45 years

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    End point title
    		 Non-inferiority of seroconversion rate at Day 11 in Cohort 3 (2-5 yrs) subjects relative to adult subjects aged 18 - 45 years [7]
    End point description
    The seroconversion rate is defined as the percentage of subjects with a 4-fold or greater rise over baseline Day 1 Serum Vibriocidal Antibody (SVA) titer against the classical Inaba biotype of V. cholerae at Day 11 following one dose of Vaxchora vaccine. The objective was to demonstrate that the paediatric seroconversion rate is non-inferior to the seroconversion rate at Day 11 in adults between the ages of 18 and 45 years.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 11
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is a comparison of solely cohort 3 and the adult bridging population. Cohorts 1 and 2 are presented seperately. The placebo groups for all cohorts was not included in this non-inferiority analysis.
    End point values
    		 Cohort 3 (active, 2-5 yrs) Adult bridging population
    Number of subjects analysed
    103
    2687
    Units: % of participants
    number (confidence interval 98.3%)
        % seroconverted
    98.1 (91.5 to 99.6)
    93.5 (92.3 to 94.6)
    Statistical analysis title
    		 Difference in % Seroconversion at Day 11, Cohort 3
    Statistical analysis description
    Non-inferiority was determined using the Newcombe method of determining the difference between two independent binomial distributions. Multiple comparison adjustment for co-primary endpoints allotted alpha=0.033 to this comparison. The lower limit of the 96.7% CI needed to be greater than -10 percentage points to prove non-inferiority
    Comparison groups
    Adult bridging population v Cohort 3 (active, 2-5 yrs)
    Number of subjects included in analysis
    2790
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    4.5
    Confidence interval
         level
    		 96.7%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 6.4
    Notes
    [8] - Newcombe method of determining the difference between two independent binomial distributions

    Secondary: Seroconversion at Day 29, 91 and 181, Cohort 1

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    End point title
    		 Seroconversion at Day 29, 91 and 181, Cohort 1 [9]
    End point description
    The seroconversion rate is defined as the percentage of subjects with a 4-fold or greater rise over baseline Day 1 in Serum Vibriocidal Antibody (SVA) titer against the classical Inaba biotype of V. cholerae at Day 29, 91 and 181 following one dose of Vaxchora vaccine.
    End point type
    Secondary
    End point timeframe
    Day 29, 91 and 181
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint result is solely for cohort 1, which had SVA values for Day 29, 91 and 181. Cohorts 2 and 3 are presented separately for Day 29, which was the last SVA result for these cohorts. The adult bridging population is not included as it was for comparison to Day 11 seroconversion only.
    End point values
    		 Cohort 1 (active, 12-17 yrs) Cohort 1 (placebo, 12-17 yrs)
    Number of subjects analysed
    156
    23
    Units: % of Participants
    number (confidence interval 95%)
        Day 29 % Seroconversion
    100 (97.6 to 100)
    0.0 (0.0 to 14.3)
        Day 91 % Seroconversion
    85.6 (79.2 to 90.3)
    0.0 (0.0 to 14.3)
        Day 181 % Seroconversion
    73.5 (66.0 to 79.9)
    0.0 (0.0 to 15.5)
    Statistical analysis title
    		 Seroconversion at Day 29, 91 & 181, Cohort 1
    Statistical analysis description
    Fisher’s exact test was used to compare Vaxchora vaccine to placebo on the percent of subjects who seroconverted. For Vaxchora vs placebo within each cohort at each Day on study timepoint, the p-value was the same (p<0.0001).
    Comparison groups
    Cohort 1 (placebo, 12-17 yrs) v Cohort 1 (active, 12-17 yrs)
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Seroconversion at Day 29, Cohort 2

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    End point title
    		 Seroconversion at Day 29, Cohort 2 [10]
    End point description
    The seroconversion rate is defined as the percentage of subjects with a 4-fold or greater rise over baseline Day 1 in Serum Vibriocidal Antibody (SVA) titer against the classical Inaba biotype of V. cholerae at Day 29 following one dose of Vaxchora vaccine.
    End point type
    Secondary
    End point timeframe
    Day 29
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint result is solely for cohort 2 at Day 29. Cohorts 1 and 3 are presented separately. The adult bridging population is not included as it was for comparison to Day 11 seroconversion only.
    End point values
    		 Cohort 2 (active, 6-11 yrs) Cohort 2 (placebo, 6-11 yrs)
    Number of subjects analysed
    138
    23
    Units: % of Participants
    number (confidence interval 95%)
        Day 29 % Seroconversion
    94.9 (89.9 to 97.5)
    4.3 (0.8 to 21.0)
    Statistical analysis title
    		 Seroconversion at Day 29, Cohort 2
    Statistical analysis description
    Fisher’s exact test was used to compare Vaxchora vaccine to placebo on the percent of subjects who seroconverted. For Vaxchora vs placebo within each cohort at each Day on study timepoint, the p-value was the same (p<0.0001).
    Comparison groups
    Cohort 2 (active, 6-11 yrs) v Cohort 2 (placebo, 6-11 yrs)
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Seroconversion at Day 29, Cohort 3

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    End point title
    		 Seroconversion at Day 29, Cohort 3 [11]
    End point description
    The seroconversion rate is defined as the percentage of subjects with a 4-fold or greater rise over baseline Day 1 in Serum Vibriocidal Antibody (SVA) titer against the classical Inaba biotype of V. cholerae at Day 29 following one dose of Vaxchora vaccine.
    End point type
    Secondary
    End point timeframe
    Day 29
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint result is solely for cohort 3 on Day 29. Cohorts 1 and 2 are presented separately. The adult bridging population is not included as it was for comparison to Day 11 seroconversion only.
    End point values
    		 Cohort 3 (active, 2-5 yrs) Cohort 3 (placebo, 2-5 yrs)
    Number of subjects analysed
    98
    18
    Units: % of Participants
    number (confidence interval 95%)
        Day 29 % Seroconversion
    93.9 (87.3 to 97.2)
    0.0 (0.0 to 17.6)
    Statistical analysis title
    		 Seroconversion at Day 29, Cohort 3
    Statistical analysis description
    Fisher’s exact test was used to compare Vaxchora vaccine to placebo on the percent of subjects who seroconverted. For Vaxchora vs placebo within each cohort at each Day on study timepoint, the p-value was the same (p<0.0001).
    Comparison groups
    Cohort 3 (active, 2-5 yrs) v Cohort 3 (placebo, 2-5 yrs)
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Seroconversion in cohort 1 at Days 365, 547 and 730

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    End point title
    		 Seroconversion in cohort 1 at Days 365, 547 and 730
    End point description
    The seroconversion rate is defined as the percentage of subjects with a 4-fold or greater rise over baseline Day 1 in Serum Vibriocidal Antibody (SVA) titer against the classical Inaba biotype of V. cholerae at Day 365, 547 and 730 following one dose of Vaxchora vaccine.
    End point type
    Secondary
    End point timeframe
    Day 365, 547 and 730
    End point values
    		 Cohort 1 Long-term (active, 12-17 yrs)
    Number of subjects analysed
    73
    Units: % of Participants
    number (confidence interval 95%)
        Day 365 % Seroconversion (N=70)
    68.6 (57.0 to 78.2)
        Day 547 % Seroconversion (N=67)
    73.1 (61.5 to 82.3)
        Day 730 % Seroconversion (N=62)
    64.5 (52.1 to 75.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events were collected for 28 days post vaccination. Serious adverse events were followed until the end of the end of the subject's participation in the study (2 years for adolescents in the long term sub-study and 6 months for all others).
    Adverse event reporting additional description
    All SAEs are included in the summaries; Other Non-serious AEs collected through 28 days post vaccination and reaching a threshold of 2% are included. Solicited adverse events were collected for daily for 8 consecutive days following vaccination (Days 1-8). Events that continued past Day 8 were recorded as unsolicited adverse events.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Cohort 1 (active, 12-17 yrs)
    Reporting group description
    		 Subjects aged 12 - 17 were administered a 100 mL oral dose of Vaxchora (Cholera Vaccine, live attenuated, oral) on Day 1, and had study visits on Day 11, 29, 91 and 181.

    Reporting group title
    Cohort 1 (placebo, 12-17 yrs)
    Reporting group description
    		 Subjects aged 12 - 17 were administered a 100 mL oral dose of placebo on Day 1, and had study visits on Day 11, 29, 91 and 181.

    Reporting group title
    Cohort 2 (active, 6-11 yrs)
    Reporting group description
    		 Subjects aged 6 - 11 were administered a 100 mL oral dose of Vaxchora (Cholera Vaccine, live attenuated, oral) on Day 1, and had study visits on Day 11, 29, 91 and 181

    Reporting group title
    Cohort 2 (placebo, 6-11 yrs)
    Reporting group description
    		 Subjects aged 6 - 11 were administered a 100 mL oral dose of placebo on Day 1, and had study visits on Day 11, 29, 91 and 181.

    Reporting group title
    Cohort 3 (active, 2-5 yrs)
    Reporting group description
    		 Subjects aged 2 - 5 were administered a 50 mL oral dose of Vaxchora (Cholera Vaccine, live attenuated, oral) on Day 1, and had study visits on Day 11, 29, 91 and 181

    Reporting group title
    Cohort 3 (placebo, 2-5 yrs)
    Reporting group description
    		 Subjects aged 2 - 5 were administered a 50 mL oral dose of placebo on Day 1, and had study visits on Day 11, 29, 91 and 181.

    Serious adverse events
    		 Cohort 1 (active, 12-17 yrs) Cohort 1 (placebo, 12-17 yrs) Cohort 2 (active, 6-11 yrs) Cohort 2 (placebo, 6-11 yrs) Cohort 3 (active, 2-5 yrs) Cohort 3 (placebo, 2-5 yrs)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 165 (2.42%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    0 / 146 (0.00%)
    1 / 26 (3.85%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Intentional overdose
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    0 / 146 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    0 / 146 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    0 / 146 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Local Swelling
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    0 / 146 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    0 / 146 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    0 / 146 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Cohort 1 (active, 12-17 yrs) Cohort 1 (placebo, 12-17 yrs) Cohort 2 (active, 6-11 yrs) Cohort 2 (placebo, 6-11 yrs) Cohort 3 (active, 2-5 yrs) Cohort 3 (placebo, 2-5 yrs)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    116 / 165 (70.30%)
    13 / 24 (54.17%)
    93 / 157 (59.24%)
    15 / 25 (60.00%)
    74 / 146 (50.68%)
    12 / 26 (46.15%)
    Injury, poisoning and procedural complications
    Laceration - unsolicited
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 24 (4.17%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    0 / 146 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Joint Injury - unsolicited
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    1 / 25 (4.00%)
    0 / 146 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Arthropod bite - unsolicited
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    0 / 146 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Headache - unsolicited
         subjects affected / exposed
    4 / 165 (2.42%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    0 / 146 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    0
    Headache - solicited
         subjects affected / exposed
    74 / 165 (44.85%)
    11 / 24 (45.83%)
    41 / 157 (26.11%)
    6 / 25 (24.00%)
    13 / 146 (8.90%)
    2 / 26 (7.69%)
         occurrences all number
    191
    18
    77
    11
    18
    3
    General disorders and administration site conditions
    Fatigue - unsolicited
         subjects affected / exposed
    4 / 165 (2.42%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    5 / 146 (3.42%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    0
    0
    5
    0
    Vessel puncture site pain - unsolicited
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    1 / 25 (4.00%)
    0 / 146 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Fatigue - solicited
    Additional description: Solicited as tiredness
         subjects affected / exposed
    67 / 165 (40.61%)
    9 / 24 (37.50%)
    55 / 157 (35.03%)
    8 / 25 (32.00%)
    45 / 146 (30.82%)
    6 / 26 (23.08%)
         occurrences all number
    170
    30
    123
    17
    108
    13
    Pyrexia - solicited
    Additional description: Solicited as fever
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 24 (0.00%)
    5 / 157 (3.18%)
    1 / 25 (4.00%)
    3 / 146 (2.05%)
    1 / 26 (3.85%)
         occurrences all number
    4
    0
    6
    1
    4
    3
    Gastrointestinal disorders
    Loose Stool - unsolicited
         subjects affected / exposed
    23 / 165 (13.94%)
    5 / 24 (20.83%)
    18 / 157 (11.46%)
    0 / 25 (0.00%)
    8 / 146 (5.48%)
    2 / 26 (7.69%)
         occurrences all number
    30
    6
    19
    0
    8
    2
    Rectal tenesmus - unsolicited
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    1 / 25 (4.00%)
    0 / 146 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Vomiting - unsolicited
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    3 / 146 (2.05%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    Diarrhoea - unsolicited
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    0 / 146 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nausea - solicited
         subjects affected / exposed
    37 / 165 (22.42%)
    6 / 24 (25.00%)
    22 / 157 (14.01%)
    4 / 25 (16.00%)
    10 / 146 (6.85%)
    4 / 26 (15.38%)
         occurrences all number
    69
    16
    37
    11
    14
    4
    Vomiting - solicited
         subjects affected / exposed
    9 / 165 (5.45%)
    0 / 24 (0.00%)
    7 / 157 (4.46%)
    0 / 25 (0.00%)
    2 / 146 (1.37%)
    3 / 26 (11.54%)
         occurrences all number
    14
    0
    12
    0
    2
    3
    Diarrhoea - solicited
         subjects affected / exposed
    6 / 165 (3.64%)
    1 / 24 (4.17%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    1 / 146 (0.68%)
    1 / 26 (3.85%)
         occurrences all number
    7
    1
    0
    0
    1
    1
    Abdominal pain - solicited
         subjects affected / exposed
    62 / 165 (37.58%)
    4 / 24 (16.67%)
    43 / 157 (27.39%)
    6 / 25 (24.00%)
    25 / 146 (17.12%)
    4 / 26 (15.38%)
         occurrences all number
    130
    10
    83
    15
    53
    7
    Skin and subcutaneous tissue disorders
    Dermatitis contact - unsolicited
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    1 / 25 (4.00%)
    0 / 146 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    Insomnia - unsolicited
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    1 / 25 (4.00%)
    0 / 146 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Infections and infestations
    Upper respiratory tract infection - unsolicited
         subjects affected / exposed
    7 / 165 (4.24%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    6 / 146 (4.11%)
    3 / 26 (11.54%)
         occurrences all number
    7
    0
    0
    0
    6
    3
    Furuncle - unsolicited
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 24 (4.17%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    0 / 146 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nasopharyngitis - unsolicited
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    2 / 25 (8.00%)
    3 / 146 (2.05%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    2
    3
    0
    Otitis media - unsolicited
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    1 / 25 (4.00%)
    0 / 146 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Ear infection - unsolicited
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    3 / 146 (2.05%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    Bronchitis - unsolicited
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    1 / 146 (0.68%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite - unsolicited
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 24 (0.00%)
    0 / 157 (0.00%)
    0 / 25 (0.00%)
    3 / 146 (2.05%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    Decreased Appetite - solicited
    Additional description: Solicited as lack of appetite.
         subjects affected / exposed
    48 / 165 (29.09%)
    3 / 24 (12.50%)
    24 / 157 (15.29%)
    5 / 25 (20.00%)
    28 / 146 (19.18%)
    3 / 26 (11.54%)
         occurrences all number
    112
    8
    47
    11
    63
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 May 2017
    The protocol was revised to remove Canada as a location for this trial, to further define the statistical analysis, to add exclusion criteria consistent with other studies of Vaxchora vaccine and to remove a planned interim analysis.
    15 Nov 2017
    The protocol was revised to increase the number of subjects in Cohort 3 (in anticipation of a high rate of inevaluable subjects), to include the collection of adverse events through 6 months post-vaccination in Placebo-Crossover subjects, and to allow for an interim analysis following completion of Cohorts 1 and 2, in order to facilitate a marketing application in Europe.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    24 Aug 2017
    Study halt 1 occurred on August 24, 2017 in response to an unrelated Grade 4 fever in one subject. The Investigator assessed the event to be non-life threatening and it did not meet any SAE criteria. The SMC was notified of this event and a temporary halt on all Day 1 vaccinations was instituted. The SMC convened with PaxVax for further review of safety information. The halt was lifted after one day, with the SMC recommending no further modifications to the study protocol. The event that triggered this temporary halt did not meet any stopping rule criteria.
    25 Aug 2017
    31 Aug 2017
    Study halt 2 occurred on August 31, 2017 in response to 2 events of severe diarrhea in two subjects assessed as possibly related to vaccination. The events met the criteria of the study stopping rules. The SMC was notified of this event and a temporary halt on all Day 1 vaccinations was instituted. The SMC convened with PaxVax for further review of safety information. The halt was lifted after 22 days, with the SMC recommending no further modifications to the study protocol.
    21 Sep 2017
    20 Oct 2017
    Study halt 3 occurred on October 20, 2017 in response to an event of severe fever in one subject, assessed as possibly related to vaccination, and an unrelated SAE (lower limb fracture) in another subject. These events met the criteria of the study stopping rules. The SMC was notified of these events and a temporary halt on all Day 1 vaccinations was instituted. The SMC convened with PaxVax for further review of safety information. The halt was lifted after 4 days, with the SMC recommending no further modification to the study protocol.
    24 Oct 2017
    06 Nov 2017
    Study halt 4 occurred on November 6, 2017 in response to events of severe vomiting and diarrhea in one subject, assessed as possibly related to vaccination. These events met the criteria of the study stopping rules. The SMC was notified of these events and a temporary halt on all Day 1 vaccinations was instituted. The SMC convened with PaxVax for further review of safety information. The halt was lifted after 4 days, with the SMC recommending no further modification to the study protocol.
    10 Nov 2017
    18 Jan 2019
    Study halt 5 occurred on January 18, 2019 in response to an event of seizure disorder and hospitalization due to worsening of seizures in one subject assessed as not related to vaccination. These events met the criteria of the study stopping rules. A de facto halt on the one remaining placebo-crossover vaccination was instituted over the subsequent weekend period. The SMC Chair was notified of this event and the halt was lifted after 20 days. No modifications to the protocol were recommended.
    07 Feb 2019

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31769402
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