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    Clinical Trial Results:
    A Phase 2, partial blind, randomized, placebo-controlled, multicenter study to evaluate the safety and immunogenicity of two novel live attenuated serotype 2 oral poliovirus vaccines candidates, in healthy adults previously vaccinated with oral polio vaccine (OPV) or inactivated polio vaccine (IPV), compared with historical controls given Sabin OPV2 or placebo.

    Summary
    EudraCT number
    		 2018-001684-22
    Trial protocol
    		 BE  
    Global end of trial date
    08 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jun 2022
    First version publication date
    26 Jun 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    UAM4
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04544787
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Antwerp
    Sponsor organisation address
    Universiteitsplein 1, Wilrijk, Belgium, 2610
    Public contact
    Prof.Dr.PhD. Pierre Van Damme, University of Antwerp, +32 (0)32652538, pierre.vandamme@uantwerpen.be
    Scientific contact
    Prof.Dr.PhD. Pierre Van Damme, University of Antwerp, +32 (0)32652538, pierre.vandamme@uantwerpen.be
    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
    08 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    08 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study are - To assess the safety (serious adverse events [SAEs] and severe adverse events [AEs]) of novel monovalent live attenuated oral serotype 2 poliovirus vaccine (nOPV2) candidate 1 and novel monovalent live attenuated oral serotype 2 poliovirus vaccine (nOPV2) candidate 2 in healthy OPV-vaccinated adults, relative to historical controls given Sabin OPV2; - To compare the immunogenicity (seroprotection rate) of novel monovalent live attenuated oral serotype 2 poliovirus vaccine (nOPV2) candidate 1 and novel monovalent live attenuated oral serotype 2 poliovirus vaccine (nOPV2) candidate 2 in healthy OPV-vaccinated adults to historical controls given Sabin OPV2; - To assess the safety (serious adverse events [SAEs] and severe adverse events [AEs]) of nOPV2 candidate 1 and nOPV2 candidate 2 in healthy IPV-only vaccinated adults, compared with placebo.
    Protection of trial subjects
    To reduce the likelihood that nOPV2 candidate vaccine strains or their genetic variants could be transmitted to unintended recipients who are not vaccinated for polio or who are immunocompromised, study subjects were only eligible for inclusion in the study if they -have received at least 3 doses of OPV or IPV in the past. -have their residence in Belgium -are willing to sign a code of conduct referring to the inclusion/exclusion criteria, rules of the protocol and hygienic measures as well as travel restrictions. -do not have any confirmed or suspected immunosuppressive or immunodeficiency condition, have been treated with immunosuppressant drugs or other immune-modifying drugs for longer than 14 days within 6 months prior to the first vaccine dose or have such use planned during the study. -will not have household or professional contact with known immunosuppressed people or people without full polio vaccination during the whole study duration, or have professional contact with children under 6 months old during the whole study duration. and excluded if: -Any travel to polio endemic countries or countries with evidence of recent (within last 6 months) wild or vaccine-derived poliovirus circulation during the total duration of the study; -Professional handling of food, catering activities (e.g. working in restaurant kitchen, bakery, ..) during the total duration of the study; If type 2 virus shedding is detected by PCR on 1 of the 3 last stool samples study duration for this individual will be extended and subject asked to further collect 3 consecutive stool samples every 3 weeks after the last pp sample until shedding is PCR negative on 3 consecutive stool samples. Travel/other restrictions described above will continue to apply until end of shedding is reached. Additional risk assessment measure: household contact monitoring will be offered in case of extended shedding (PCR of at least 1 of the FU samples after D42 following last vaccination
    Background therapy
    		 -
    Evidence for comparator
    		 Due to the withdrawal of Sabin mOPV2 and prohibition of its use from April 2016 onwards, well before the availability of nOPV2 for clinical testing, Phase 4 trials have been conducted with Sabin mOPV2 to provide control data on safety, immunogenicity, against which data for nOPV2 in subsequent Phase I and II studies will be evaluated and compared. The Phase 4 trials of Sabin mOPV2 were designed to parallel the expected design of the Phase 1 and 2 nOPV2 studies with respect to overall design, inclusion of similar study cohorts. The Phase 2 study is designed to evaluate the safety and immunogenicity of both nOPV2 vaccines in adults before testing in young children and then infants. The primary objectives of the Phase 2 study include the general safety and immunogenicity of the two candidate vaccines, primarily based on comparison with historical data obtained in the Phase 4 study of Sabin mOPV2 for OPV-vaccinated subjects, in order to establish non-inferior immunogenicity and acceptable safety profile. Assessment of the general safety of the 2 candidate vaccines in IPV-only vaccinated subjects will be based on comparison with data from a placebo group.
    Actual start date of recruitment
    01 Sep 2018
    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
    Belgium: 250
    Worldwide total number of subjects
    250
    EEA total number of subjects
    250
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    250
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This study was conducted at 2 centers in Belgium. 277 volunteers were screened between Oct2018, and Feb2019, and 250 participants were enrolled. Eligible participants were healthy adults aged 18–50 years with documented history of at least 3 polio vaccinations with either oral polio vaccine (OPV) or inactivated polio vaccine (IPV)

    Pre-assignment
    Screening details
    		 nOPV2-c2 was prioritized so first 100 OPV-vaccinated adults were randomized 1:1 to Groups 3 and 4 to receive nOPV2-c2. Next 100 OPV-vaccinated adults were randomized 1:1 to Groups 1 and 2 to receive nOPV2-c1. Parallel randomization of IPV-vaccinated adults: 2:1 to Group 6 or 7 until Group 6 was complete, then 2:1 randomization for Groups 5 +7

    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, Assessor
    Blinding implementation details
    All OPV-vaccinated subjects will receive one of the nOPV2 candidates in a single blind manner and all IPV- vaccinated subjects will receive one of the nOPV2 candidates or placebo in a double-blinded manner. For the whole study duration all subjects and blinded study staff responsible for safety evaluation of IPV-subjects will not have any information of what has been administered. As the placebo can be distinguished from the vaccine candidates in packaging and color, reception of the vaccines,

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1: OPV-vaccinated - One dose of Novel OPV2 Candidate 1
    Arm description
    		 Participants previously vaccinated with oral polio vaccine (OPV) received one dose of novel OPV2 candidate 1 on Day 0, administered orally as six drops (0.3 mL total)
    Arm type
    		 Experimental

    Investigational medicinal product name
    nOPV2 candidate 1 (S2/cre5/S15domV/rec1/hifi3)
    Investigational medicinal product code
    nOPV2 candidate1
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Participants previously vaccinated with OPV received one dose of novel oral polio vaccine type 2 (nOPV2)candidate 1 on study Day 0, administered orally as six drops (0.3 mL total).

    Arm title
    		 Group 2: OPV-vaccinated - Two doses of Novel OPV2 Candidate 1
    Arm description
    		 Participants previously vaccinated with oral polio vaccine (OPV) received two doses of novel OPV2 candidate 1, 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total)
    Arm type
    		 Experimental

    Investigational medicinal product name
    nOPV2 candidate 1 (S2/cre5/S15domV/rec1/hifi3)
    Investigational medicinal product code
    nOPV2 candidate1
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Participants previously vaccinated with OPV received two doses of novel OPV2 candidate 1 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total).

    Arm title
    		 Group 3: OPV-vaccinated - One dose of Novel OPV2 Candidate 2
    Arm description
    		 Participants previously vaccinated with OPV received one dose of novel OPV2 candidate 2 on study Day 0, administered orally as six drops (0.3 mL total).
    Arm type
    		 Experimental

    Investigational medicinal product name
    nOPV2 candidate 2 (S2/S15domV/CpG40)
    Investigational medicinal product code
    nOPV2 candidate 2
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Participants previously vaccinated with OPV received one dose of novel OPV2 candidate 2 on study Day 0, administered orally as six drops (0.3 mL total; approximately 10# CCID50).

    Arm title
    		 Group 4: OPV-vaccinated - Two doses of Novel OPV2 Candidate 2
    Arm description
    		 Participants previously vaccinated OPV received two doses novel OPV2 candidate 2 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL)
    Arm type
    		 Experimental

    Investigational medicinal product name
    nOPV2 candidate 2 (S2/S15domV/CpG40)
    Investigational medicinal product code
    nOPV2 candidate 2
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Participants previously vaccinated with OPV received two doses of novel OPV2 candidate 2 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total; approximately 10# CCID50).

    Arm title
    		 Group 5: IPV-vaccinated - Two doses of Novel OPV2 Candidate 1
    Arm description
    		 Participants previously vaccinated with inactivated polio vaccine (IPV) received two doses of novel OPV2 candidate 1 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL).
    Arm type
    		 Experimental

    Investigational medicinal product name
    nOPV2 candidate 1 (S2/cre5/S15domV/rec1/hifi3)
    Investigational medicinal product code
    nOPV2 candidate1
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Participants previously vaccinated with only IPV received two doses of novel OPV2 candidate 1 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL).

    Arm title
    		 Group 6: IPV-vaccinated - Two doses of Novel OPV2 Candidate 2
    Arm description
    		 Participants previously vaccinated with IPV received two doses of novel OPV2 candidate 2 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total; approximately 10# CCID50)
    Arm type
    		 Experimental

    Investigational medicinal product name
    nOPV2 candidate 2 (S2/S15domV/CpG40)
    Investigational medicinal product code
    nOPV2 candidate 2
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Participants previously vaccinated with only IPV received two doses of novel OPV2 candidate 2 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL).

    Arm title
    		 Group 7: IPV-vaccinated - Two doses of placebo
    Arm description
    		 Participants previously vaccinated with IPV received two doses of placebo 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sirupus Simplex, Propylenglycolum, Ph.Eur.
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Participants previously vaccinated with only IPV received two doses of placebo 28 days apart (Day 0 and Day 28), administered orally as six drops.

    Number of subjects in period 1
    		Group 1: OPV-vaccinated - One dose of Novel OPV2 Candidate 1 Group 2: OPV-vaccinated - Two doses of Novel OPV2 Candidate 1 Group 3: OPV-vaccinated - One dose of Novel OPV2 Candidate 2 Group 4: OPV-vaccinated - Two doses of Novel OPV2 Candidate 2 Group 5: IPV-vaccinated - Two doses of Novel OPV2 Candidate 1 Group 6: IPV-vaccinated - Two doses of Novel OPV2 Candidate 2 Group 7: IPV-vaccinated - Two doses of placebo
    Started
    50
    50
    50
    50
    17
    16
    17
    Completed
    50
    50
    50
    50
    17
    16
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: OPV-vaccinated - One dose of Novel OPV2 Candidate 1
    Reporting group description
    		 Participants previously vaccinated with oral polio vaccine (OPV) received one dose of novel OPV2 candidate 1 on Day 0, administered orally as six drops (0.3 mL total)

    Reporting group title
    Group 2: OPV-vaccinated - Two doses of Novel OPV2 Candidate 1
    Reporting group description
    		 Participants previously vaccinated with oral polio vaccine (OPV) received two doses of novel OPV2 candidate 1, 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total)

    Reporting group title
    Group 3: OPV-vaccinated - One dose of Novel OPV2 Candidate 2
    Reporting group description
    		 Participants previously vaccinated with OPV received one dose of novel OPV2 candidate 2 on study Day 0, administered orally as six drops (0.3 mL total).

    Reporting group title
    Group 4: OPV-vaccinated - Two doses of Novel OPV2 Candidate 2
    Reporting group description
    		 Participants previously vaccinated OPV received two doses novel OPV2 candidate 2 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL)

    Reporting group title
    Group 5: IPV-vaccinated - Two doses of Novel OPV2 Candidate 1
    Reporting group description
    		 Participants previously vaccinated with inactivated polio vaccine (IPV) received two doses of novel OPV2 candidate 1 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL).

    Reporting group title
    Group 6: IPV-vaccinated - Two doses of Novel OPV2 Candidate 2
    Reporting group description
    		 Participants previously vaccinated with IPV received two doses of novel OPV2 candidate 2 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total; approximately 10# CCID50)

    Reporting group title
    Group 7: IPV-vaccinated - Two doses of placebo
    Reporting group description
    		 Participants previously vaccinated with IPV received two doses of placebo 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total)

    Reporting group values
    		 Group 1: OPV-vaccinated - One dose of Novel OPV2 Candidate 1 Group 2: OPV-vaccinated - Two doses of Novel OPV2 Candidate 1 Group 3: OPV-vaccinated - One dose of Novel OPV2 Candidate 2 Group 4: OPV-vaccinated - Two doses of Novel OPV2 Candidate 2 Group 5: IPV-vaccinated - Two doses of Novel OPV2 Candidate 1 Group 6: IPV-vaccinated - Two doses of Novel OPV2 Candidate 2 Group 7: IPV-vaccinated - Two doses of placebo Total
    Number of subjects
    		 50 50 50 50 17 16 17 250
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31 ± 10 31 ± 10 32 ± 10 34 ± 10 23 ± 10 31 ± 9 24 ± 9 -
    Gender categorical
    Units: Subjects
        Female
    		 22 29 28 32 11 13 14 149
        Male
    		 28 21 22 18 6 3 3 101
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 49 49 49 49 16 16 15 243
        Asian
    		 0 0 1 0 0 0 0 1
        Black or African American
    		 0 0 0 0 0 0 1 1
        other
    		 1 1 0 1 1 0 1 5
    Number of prior OPV vaccinations
    Units: Subjects
        None
    		 0 0 0 0 17 16 17 50
        Three
    		 49 50 41 40 0 0 0 180
        Four
    		 1 0 9 9 0 0 0 19
        Five
    		 0 0 0 1 0 0 0 1
    Number of prior IPV vaccinations
    Units: Subjects
        None
    		 46 49 48 47 0 0 0 190
        One
    		 4 1 2 3 0 0 0 10
        Four
    		 0 0 0 0 6 4 10 20
        Five
    		 0 0 0 0 10 5 5 20
        Six or more
    		 0 0 0 0 1 7 2 10

    End points

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    End points reporting groups
    Reporting group title
    Group 1: OPV-vaccinated - One dose of Novel OPV2 Candidate 1
    Reporting group description
    		 Participants previously vaccinated with oral polio vaccine (OPV) received one dose of novel OPV2 candidate 1 on Day 0, administered orally as six drops (0.3 mL total)

    Reporting group title
    Group 2: OPV-vaccinated - Two doses of Novel OPV2 Candidate 1
    Reporting group description
    		 Participants previously vaccinated with oral polio vaccine (OPV) received two doses of novel OPV2 candidate 1, 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total)

    Reporting group title
    Group 3: OPV-vaccinated - One dose of Novel OPV2 Candidate 2
    Reporting group description
    		 Participants previously vaccinated with OPV received one dose of novel OPV2 candidate 2 on study Day 0, administered orally as six drops (0.3 mL total).

    Reporting group title
    Group 4: OPV-vaccinated - Two doses of Novel OPV2 Candidate 2
    Reporting group description
    		 Participants previously vaccinated OPV received two doses novel OPV2 candidate 2 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL)

    Reporting group title
    Group 5: IPV-vaccinated - Two doses of Novel OPV2 Candidate 1
    Reporting group description
    		 Participants previously vaccinated with inactivated polio vaccine (IPV) received two doses of novel OPV2 candidate 1 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL).

    Reporting group title
    Group 6: IPV-vaccinated - Two doses of Novel OPV2 Candidate 2
    Reporting group description
    		 Participants previously vaccinated with IPV received two doses of novel OPV2 candidate 2 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total; approximately 10# CCID50)

    Reporting group title
    Group 7: IPV-vaccinated - Two doses of placebo
    Reporting group description
    		 Participants previously vaccinated with IPV received two doses of placebo 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total)

    Subject analysis set title
    Group 1+2: OPV-vaccinated - novel OPV2 candidate 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously vaccinated with OPV received vaccination with novel OPV2 candidate 1 on study Day 0.

    Subject analysis set title
    Group 3+4: OPV-vaccinated - novel OPV2 candidate 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously vaccinated with OPV received vaccination with novel OPV2 candidate 2 on study Day 0

    Subject analysis set title
    Group 2: OPV-vaccinated - novel OPV2 candidate 1 Post-dose 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously vaccinated with OPV received a second vaccination with novel OPV2 candidate 1 on Day 28.

    Subject analysis set title
    Group 4: OPV-vaccinated - novel OPV2 Candidate 2 Post-dose 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously vaccinated with OPV received a second vaccination with novel OPV2 candidate 2 on Day 28.

    Subject analysis set title
    Group 5: IPV-vaccinated - Novel OPV2 Candidate 1 Post-dose 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously vaccinated with only IPV received a vaccination with novel OPV2 candidate 1 on Day 0.

    Subject analysis set title
    Group 5: IPV-vaccinated - Novel OPV2 Candidate 1 Post-dose 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously vaccinated with only IPV received a second vaccination with novel OPV2 candidate 1 on Day 28.

    Subject analysis set title
    Group 6: IPV-vaccinated - novel OPV candidate 2 Post-dose 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously vaccinated with only IPV received a vaccination with novel OPV2 candidate 2 on Day 0.

    Subject analysis set title
    Group 6: IPV-vaccinated - novel OPV candidate 2 Post-dose 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously vaccinated with only IPV received a second vaccination with novel OPV2 candidate 2 on Day 28.

    Subject analysis set title
    Group 7: IPV-vaccinated - Placebo Post-dose 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously vaccinated with only IPV received a vaccination with placebo on Day 0.

    Subject analysis set title
    Group 7: IPV-vaccinated - Placebo Post-dose 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously vaccinated with only IPV received a second vaccination with placebo on Day 28.

    Subject analysis set title
    Group 1+2: OPV-vaccinated - Novel OPV2 candidate 1 Post-dose 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously vaccinated with OPV received vaccination with novel OPV2 candidate 1 on study Day 0.

    Subject analysis set title
    Group 3+4: OPV-vaccinated - novel OPV2 candidate 2 Post-dose 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously vaccinated with OPV received vaccination with novel OPV2 candidate 2 on study Day 0.

    Subject analysis set title
    Group 5: IPV-vaccinated - Novel OPV2 Candidate 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously vaccinated with only IPV received a vaccination with novel OPV2 candidate 1 on Day 0.

    Subject analysis set title
    Group 6: IPV-vaccinated - Novel OPV2 Candidate 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously vaccinated with only IPV received a vaccination with novel OPV2 candidate 2 on Day 0.

    Subject analysis set title
    Group 7: IPV-vaccinated - Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously vaccinated with only IPV received a vaccination with placebo on Day 0.

    Primary: Number of Participants With Serious Adverse Events (SAEs) and Severe Adverse Events

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    End point title
    		 Number of Participants With Serious Adverse Events (SAEs) and Severe Adverse Events
    End point description
    An SAE is any untoward medical occurrence that at any dose met any of the following conditions: • Resulted in death; • Was life-threatening; • Required inpatient hospitalization or prolongation of existing inpatient hospitalization; • Resulted in persistent or significant disability/incapacity; • Was a congenital anomaly/birth defect; • Was medically important. A solicited AE is a pre-selected sign or symptom that occurred within 7 days after each dose, whereas unsolicited AEs were collected throughout the study. Solicited AEs included headache, fatigue, myalgia, arthralgia, paresthesia, anesthesia, paralysis, nausea, vomiting, diarrhea, abdominal pain, and fever. A severe AE is an AE that prevented normal everyday activities and which was not classified as an SAE. A related AE is an AE the investigator considered probably or possibly caused by the study vaccine, meaning that there was a reasonable temporal association or the AE was not attributable to other conditions.
    End point type
    Primary
    End point timeframe
    Up to 42 days after each vaccination
    End point values
    		 Group 1: OPV-vaccinated - One dose of Novel OPV2 Candidate 1 Group 2: OPV-vaccinated - Two doses of Novel OPV2 Candidate 1 Group 3: OPV-vaccinated - One dose of Novel OPV2 Candidate 2 Group 4: OPV-vaccinated - Two doses of Novel OPV2 Candidate 2 Group 5: IPV-vaccinated - Two doses of Novel OPV2 Candidate 1 Group 6: IPV-vaccinated - Two doses of Novel OPV2 Candidate 2 Group 7: IPV-vaccinated - Two doses of placebo
    Number of subjects analysed
    50
    50
    50
    50
    17
    16
    17
    Units: participants
        Serious or Severe adverse event
    9
    16
    5
    8
    5
    6
    10
        Serious adverse events
    1
    1
    0
    1
    0
    1
    0
        Serious solicited adverse events
    0
    0
    0
    0
    0
    0
    0
        Serious unsolicited adverse events
    1
    1
    0
    1
    0
    1
    0
        Serious adverse events related to study vaccine
    0
    0
    0
    0
    0
    1
    0
        Severe adverse events
    9
    16
    5
    8
    5
    6
    10
        Severe solicited adverse events
    1
    2
    1
    2
    1
    1
    2
        Severe unsolicited adverse events
    8
    15
    4
    7
    4
    5
    9
        Severe adverse events related to study vaccine
    1
    2
    1
    2
    2
    5
    4
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The number of participants with severe solicited adverse events in the OPV-vaccinated groups who received nOPV-c1 (combined Groups 1 and 2) was compared with the corresponding endpoint from the historical monovalent OPV2 control study (UAM1, EudraCT # 2015-003325-33) using the two-sided Fisher’s exact test. In the UAM1 study, the number of participants with severe solicited adverse events was 5 out of 100.
    Comparison groups
    Group 1: OPV-vaccinated - One dose of Novel OPV2 Candidate 1 v Group 2: OPV-vaccinated - Two doses of Novel OPV2 Candidate 1
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7209
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The number of participants with severe solicited adverse events in the OPV-vaccinated groups who received nOPV-c2 (combined Groups 3 and 4) was compared with the corresponding endpoint from the historical monovalent OPV2 control study (UAM1, EudraCT # 2015-003325-33) using the two-sided Fisher’s exact test. In the UAM1 study, the number of participants with severe solicited adverse events was 5 out of 100.
    Comparison groups
    Group 3: OPV-vaccinated - One dose of Novel OPV2 Candidate 2 v Group 4: OPV-vaccinated - Two doses of Novel OPV2 Candidate 2
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7209
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    The number of participants with severe unsolicited adverse events in the OPV-vaccinated groups who received nOPV-c1 (combined Groups 1 and 2) was compared with the corresponding endpoint from the historical monovalent OPV2 control study (UAM1, EudraCT # 2015-003325-33) using the two-sided Fisher’s exact test. In the UAM1 study, the number of participants with severe unsolicited adverse events was 17 out of 100.
    Comparison groups
    Group 1: OPV-vaccinated - One dose of Novel OPV2 Candidate 1 v Group 2: OPV-vaccinated - Two doses of Novel OPV2 Candidate 1
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3769
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    The number of participants with severe unsolicited adverse events in the OPV-vaccinated groups who received nOPV-c2 (combined Groups 3 and 4) was compared with the corresponding endpoint from the historical monovalent OPV2 control study (UAM1, EudraCT # 2015-003325-33) using the two-sided Fisher’s exact test. In the UAM1 study, the number of participants with severe unsolicited adverse events was 17 out of 100.
    Comparison groups
    Group 3: OPV-vaccinated - One dose of Novel OPV2 Candidate 2 v Group 4: OPV-vaccinated - Two doses of Novel OPV2 Candidate 2
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3083
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    The number of participants with serious unsolicited adverse events in the OPV-vaccinated groups who received nOPV-c1 (combined Groups 1 and 2) was compared with the corresponding endpoint from the historical monovalent OPV2 control study (UAM1, EudraCT # 2015-003325-33) using the two-sided Fisher’s exact test. In the UAM1 study, the number of participants with serious unsolicited adverse events was 0 out of 100.
    Comparison groups
    Group 1: OPV-vaccinated - One dose of Novel OPV2 Candidate 1 v Group 2: OPV-vaccinated - Two doses of Novel OPV2 Candidate 1
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4975
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    The number of participants with serious unsolicited adverse events in the OPV-vaccinated groups who received nOPV-c2 (combined Groups 3 and 4) was compared with the corresponding endpoint from the historical monovalent OPV2 control study (UAM1, EudraCT # 2015-003325-33) using the two-sided Fisher’s exact test. In the UAM1 study, the number of participants with serious unsolicited adverse events was 0 out of 100.
    Comparison groups
    Group 3: OPV-vaccinated - One dose of Novel OPV2 Candidate 2 v Group 4: OPV-vaccinated - Two doses of Novel OPV2 Candidate 2
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    comparison of severe solicited adverse events
    Comparison groups
    Group 5: IPV-vaccinated - Two doses of Novel OPV2 Candidate 1 v Group 7: IPV-vaccinated - Two doses of placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    comparison of severe solicited adverse events
    Comparison groups
    Group 6: IPV-vaccinated - Two doses of Novel OPV2 Candidate 2 v Group 7: IPV-vaccinated - Two doses of placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    comparison of severe unsolicited adverse events
    Comparison groups
    Group 5: IPV-vaccinated - Two doses of Novel OPV2 Candidate 1 v Group 7: IPV-vaccinated - Two doses of placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1571
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    comparison of severe unsolicited adverse events
    Comparison groups
    Group 6: IPV-vaccinated - Two doses of Novel OPV2 Candidate 2 v Group 7: IPV-vaccinated - Two doses of placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.296
    Method
    		 Fisher exact
    Confidence interval

    Primary: Seroprotection Rate After a Single Dose of Novel OPV2 in Former OPV Recipients

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    End point title
    		 Seroprotection Rate After a Single Dose of Novel OPV2 in Former OPV Recipients
    End point description
    Measure Description: Seroprotection rate was defined as the percentage of participants with anti-type 2-specific poliovirus neutralizing antibody titers ≥ 1:8. Neutralizing antibodies against poliovirus type 2 were determined using the World Health Organization (WHO) standard microneutralization assay (WHO EPI GEN 93.9). The lower limit of quantitation (LLOQ) was 5.7 and the upper limit of quantitation (ULOQ) was 1448. Analysis Population Description: Participants in the per-protocol population previously vaccinated with OPV. The per-protocol population excluded participants with missed doses or major protocol deviations considered to have a potential impact on immunogenicity from the time of the deviation and at all time points thereafter. This endpoint was analyzed after one dose of nOPV hence Groups 1 and 2 and Groups 3 and 4 are combined for analysis, as specified in the study protocol.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0 prior to vaccination) and Day 28
    End point values
    		 Group 1+2: OPV-vaccinated - novel OPV2 candidate 1 Group 3+4: OPV-vaccinated - novel OPV2 candidate 2
    Number of subjects analysed
    98
    98
    Units: percentage or participants
    number (confidence interval 95%)
        Day 0 (pre-vaccination)
    99 (94 to 100)
    94 (87 to 98)
        Day 28
    100 (96 to 100)
    100 (96 to 100)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The seroprotection rate after 1 dose of eithervaccine candidate in the OPV-vaccinated groups (nOPV2 combined groups 1 and 2,and combined groups 3 and 4), was compared with the corresponding endpoint from the historical monovalent OPV2 (mOPV2) control study (UAM1, EudraCT # 2015-003325-33). In the UAM1 study, the observed seroprotection rate after 1 dose of mOPV2 was98% (98 out of 100 participants), with 95% confidence interval (CI) of 93-100%. Stat. Analysis 1 regards only comparison Group 1+2
    Comparison groups
    Group 1+2: OPV-vaccinated - novel OPV2 candidate 1 v Group 3+4: OPV-vaccinated - novel OPV2 candidate 2
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 7
    Notes
    [1] - The primary immunogenicity endpoint, seroprotection on Day 28 after a single dose of each vaccine candidate, was formally compared with the corresponding endpoint from UAM1 via a non-inferiority test of the difference of each of the novel candidates to the monovalent OPV2 control, mOPV2, each using one-sided α=0.025 and a non-inferiority margin of 10%, computed using two-sided α=0·05 Miettinen and Nurminen score-based CIs for inference.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The seroprotection rate after 1 dose of either vaccine candidate in the OPV-vaccinated groups (nOPV2 combined groups 1 and 2, and combined groups 3 and 4), was compared with the corresponding endpoint from the historical monovalent OPV2 control study (UAM1, EudraCT # 2015-003325-33). In the UAM1 study, the observed seroprotection rate after 1 dose of mOPV2 was 98% (98 out of 100 participants), with a 95% confidence interval (CI) of 93-100%. Stat. Analysis 2 regards only comparison Group 3+4
    Comparison groups
    Group 3+4: OPV-vaccinated - novel OPV2 candidate 2 v Group 1+2: OPV-vaccinated - novel OPV2 candidate 1
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Difference
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 7
    Notes
    [2] - The primary immunogenicity endpoint, seroprotection on Day 28 after a single dose of each vaccine candidate, was formally compared with the corresponding endpoint from UAM1 via a non-inferiority test of the difference of each of the novel candidates to the monovalent OPV2 control, mOPV2, each using one-sided α=0.025 and a non-inferiority margin of 10%, computed using two-sided α=0·05 Miettinen and Nurminen score-based CIs for inference.

    Secondary: Number of Former OPV Recipients With Solicited Adverse Events Within 7 Days of Vaccination With Novel OPV2

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    End point title
    		 Number of Former OPV Recipients With Solicited Adverse Events Within 7 Days of Vaccination With Novel OPV2
    End point description
    Measure description: Subjects completed 7-day diary cards soliciting systemic AEs and daily oral temperature. Solicited AEs: selected signs and symptoms including headache, fatigue, myalgia, arthralgia, paresthesia, anesthesia, paralysis, nausea, vomiting, diarrhea and abdominal pain, or fever defined as temperature ≥37.5°C. AEs were graded as mild (easily tolerated with minimal discomfort or temperature 37.5°C to 38.0°C), moderate (sufficiently discomforting to interfere with normal everyday activities, or temp. 38.1°C to 39.0°C), or severe (preventing normal everyday activities, or temperatures > 39.0°C). AEs were assessed by the investigator for causality. Probably related suggests that a reasonable temporal sequence of the AE with vaccine administration exists and, in the Investigator’s clinical judgment, it is likely that a causal relationship exists between the vaccine administration and the AE Population description: OPV-vaccinated subjects in total vaccinated population
    End point type
    Secondary
    End point timeframe
    Up to 7 days after each dose (Day 0-7 post-dose 1 and Day 28-35 post-dose 2)
    End point values
    		 Group 2: OPV-vaccinated - novel OPV2 candidate 1 Post-dose 2 Group 4: OPV-vaccinated - novel OPV2 Candidate 2 Post-dose 2 Group 1+2: OPV-vaccinated - Novel OPV2 candidate 1 Post-dose 1 Group 3+4: OPV-vaccinated - novel OPV2 candidate 2 Post-dose 1
    Number of subjects analysed
    100
    49
    100
    49
    Units: subjects
        Any solicited adverse event
    71
    26
    74
    21
        Mild
    45
    18
    60
    14
        Moderate
    23
    8
    12
    6
        Severe
    3
    0
    2
    1
        Probably related to vaccination
    44
    15
    37
    12
    No statistical analyses for this end point

    Secondary: Number of Former IPV Recipients With Solicited Adverse Events After Vaccination With Novel OPV2

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    End point title
    		 Number of Former IPV Recipients With Solicited Adverse Events After Vaccination With Novel OPV2
    End point description
    Measure description:Subjects completed 7-day diary cards soliciting systemic AEs and daily oral temperature. Solicited AEs comprised selected signs and symptoms including headache, fatigue, myalgia, arthralgia, paresthesia, anesthesia, paralysis, nausea, vomiting, diarrhea and abdominal pain, or fever defined as a temperature ≥37.5°C. AEs were graded as mild (easily tolerated with minimal discomfort or temperature 37.5°C to 38.0°C), moderate (sufficiently discomforting to interfere with normal everyday activities, or temp. 38.1°C to 39.0°C), or severe (preventing normal everyday activities, or temperatures > 39.0°C). AEs were assessed by the investigator for causality. Probably related suggests that a reasonable temporal sequence of the AE with vaccine administration exists and, in the Investigator’s clinical judgment, it is likely that a causal relationship exists between the vaccine administration and the AE, Population: IPV-vaccinated subjects in the total vaccinated population
    End point type
    Secondary
    End point timeframe
    7 days post-dose (Day 0-7 post-dose 1 and and Day 28-35 post-dose 2)
    End point values
    		 Group 5: IPV-vaccinated - Novel OPV2 Candidate 1 Post-dose 1 Group 5: IPV-vaccinated - Novel OPV2 Candidate 1 Post-dose 2 Group 6: IPV-vaccinated - novel OPV candidate 2 Post-dose 1 Group 6: IPV-vaccinated - novel OPV candidate 2 Post-dose 2 Group 7: IPV-vaccinated - Placebo Post-dose 1 Group 7: IPV-vaccinated - Placebo Post-dose 2
    Number of subjects analysed
    17
    17
    16
    15
    17
    16
    Units: subjects
        Any solicited adverse events
    16
    11
    13
    9
    15
    12
        Mild
    11
    8
    6
    3
    9
    7
        Moderate
    4
    3
    7
    5
    4
    5
        Severe
    1
    0
    0
    1
    2
    0
        Probably related to vaccination
    9
    8
    5
    8
    9
    5
    No statistical analyses for this end point

    Secondary: Number of Participants With Unsolicited Adverse Events

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    End point title
    		 Number of Participants With Unsolicited Adverse Events
    End point description
    Measure description: Unsolicited events comprised other signs and symptoms that participants reported through the end of the study. Each unsolicited AE was rated on a 3-point scale of increasing intensity: • Grade 1: Mild; an AE that was easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities. • Grade 2: Moderate; an AE that was sufficiently discomforting to interfere with normal everyday activities. • Grade 3: Severe; an AE that prevented normal everyday activities. Each adverse event was assessed by the investigator for causality as unrelated, unlikely, possibly, or probably related to the vaccination. Analysis Population Description: Total vaccinated population
    End point type
    Secondary
    End point timeframe
    Up to 42 days after each vaccination
    End point values
    		 Group 1: OPV-vaccinated - One dose of Novel OPV2 Candidate 1 Group 2: OPV-vaccinated - Two doses of Novel OPV2 Candidate 1 Group 3: OPV-vaccinated - One dose of Novel OPV2 Candidate 2 Group 4: OPV-vaccinated - Two doses of Novel OPV2 Candidate 2 Group 5: IPV-vaccinated - Two doses of Novel OPV2 Candidate 1 Group 6: IPV-vaccinated - Two doses of Novel OPV2 Candidate 2 Group 7: IPV-vaccinated - Two doses of placebo
    Number of subjects analysed
    50
    50
    50
    50
    17
    16
    17
    Units: subjects
        Any unsolicited adverse event
    34
    43
    38
    42
    15
    13
    17
        Mild
    8
    10
    10
    11
    3
    0
    1
        Moderate
    18
    18
    24
    24
    8
    8
    7
        Severe
    8
    15
    4
    7
    4
    5
    9
        Probably related to vaccination
    2
    2
    1
    2
    1
    2
    1
    No statistical analyses for this end point

    Secondary: Number of Former OPV Recipients With Clinically Relevant Laboratory Abnormalities Up to 28 Days After Each Vaccination

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    End point title
    		 Number of Former OPV Recipients With Clinically Relevant Laboratory Abnormalities Up to 28 Days After Each Vaccination [3]
    End point description
    Measure Description: Laboratory assessments were collected at one-week intervals from Day 0 to Day 28 (except for Day 21) and at Days 35, 42, and 56 for participants in Groups 2 and 4 who received a 2nd dose. The Investigator reviewed laboratory values outside the normal range and assessed their clinical relevance. Any clinically relevant abnormal lab values that occurred at any visit up to 28 days after the first vaccination (in combined Groups 1 and 2 and Groups 3 and 4) and up to 28 days (Day 56) after the second dose (Groups 2 and 4) are reported. Analysis Population Description: Participants in the total vaccinated population previously vaccinated with OPV.
    End point type
    Secondary
    End point timeframe
    Day 0, Day 7, Day 14, and Day 28 for Groups 1-4 and at Day 35, Day 42, and Day 56 for participants in Groups 2 and 4
    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: The endpoint for the other arms is defined as a separate endpoint in the protocol and therefore also separated reported in the endpoint: Number of Former IPV Recipients with Clinically Relevant Laboratory Abnormalities Up to 28 Days After Each Vaccination
    End point values
    		 Group 2: OPV-vaccinated - Two doses of Novel OPV2 Candidate 1 Group 4: OPV-vaccinated - Two doses of Novel OPV2 Candidate 2 Group 1+2: OPV-vaccinated - Novel OPV2 candidate 1 Post-dose 1 Group 3+4: OPV-vaccinated - novel OPV2 candidate 2 Post-dose 1
    Number of subjects analysed
    50
    50
    Units: subjects
    18
    15
    28
    30
    No statistical analyses for this end point

    Secondary: Number of Former IPV Recipients With Clinically Relevant Laboratory Abnormalities Up to 28 Days After Each Vaccination

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    End point title
    		 Number of Former IPV Recipients With Clinically Relevant Laboratory Abnormalities Up to 28 Days After Each Vaccination [4]
    End point description
    Measure Description Laboratory assessments were collected at one-week intervals from Day 0 to Day 56, except for Days 21 and 49. The Investigator reviewed laboratory values outside the normal range and assessed their clinical relevance. Any clinically relevant abnormal laboratory abnormalities that occurred at any visit up to 56 days are reported. Analysis Population Description: Participants in the total vaccinated population previously vaccinated with IPV only.
    End point type
    Secondary
    End point timeframe
    Day 0, Day 7, Day 14, Day 28, Day 35, Day 42 and Day 56
    Notes
    [4] - 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: The endpoint for the other arms is defined as a separate endpoint in the protocol and therefore also separated reported in the endpoint: Number of Former OPV Recipients with Clinically Relevant Laboratory Abnormalities Up to 28 Days After Each Vaccination
    End point values
    		 Group 5: IPV-vaccinated - Two doses of Novel OPV2 Candidate 1 Group 6: IPV-vaccinated - Two doses of Novel OPV2 Candidate 2 Group 7: IPV-vaccinated - Two doses of placebo
    Number of subjects analysed
    17
    16
    17
    Units: subjects
    4
    6
    9
    No statistical analyses for this end point

    Secondary: Anti-Poliovirus Type-2 Neutralizing Antibody Titers After A Single Dose of Novel OPV2

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    End point title
    		 Anti-Poliovirus Type-2 Neutralizing Antibody Titers After A Single Dose of Novel OPV2
    End point description
    Measure Description: Neutralizing antibodies against poliovirus type 2 were determined using the World Health Organization (WHO) standard microneutralization assay (WHO EPI GEN 93.9). The lower limit of quantitation (LLOQ) was 5.7 and the upper limit of quantitation (ULOQ) was 1448. Data were calculated on log2-transformed type 2 neutralizing titers and back transformed for the presentation below. Values shown as 1448 should be interpreted as ≥ 1448. Analysis Population Description: Per-protocol population. The per-protocol population excluded participants with missed doses or major protocol deviations considered to have a potential impact on immunogenicity from the time of the deviation and at all time points thereafter. This endpoint was analyzed after one dose of nOPV hence Groups 1 and 2 and Groups 3 and 4 are combined for analysis, as specified in the study protocol. Samples for 2 participants in Group 5 on Day 0 were mixed up and are not included in the analysis.
    End point type
    Secondary
    End point timeframe
    Day 0 and Day 28
    End point values
    		 Group 1+2: OPV-vaccinated - novel OPV2 candidate 1 Group 3+4: OPV-vaccinated - novel OPV2 candidate 2 Group 5: IPV-vaccinated - Novel OPV2 Candidate 1 Group 6: IPV-vaccinated - Novel OPV2 Candidate 2 Group 7: IPV-vaccinated - Placebo
    Number of subjects analysed
    98
    98
    17
    16
    16
    Units: titer
    median (inter-quartile range (Q1-Q3))
        Day 0 (pre-vaccination)
    324 (228 to 455)
    455 (256 to 724)
    228 (74 to 588)
    144 (26 to 446)
    91 (11 to 362)
        Day 28
    1448 (1448 to 1448)
    1152 (815 to 1448)
    1448 (1448 to 1448)
    1448 (1176 to 1448)
    51 (8 to 256)
    No statistical analyses for this end point

    Secondary: Seroprotection Rate 28 Days After Two Doses of Novel OPV2 in Former OPV Recipients

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    End point title
    		 Seroprotection Rate 28 Days After Two Doses of Novel OPV2 in Former OPV Recipients [5]
    End point description
    Measure Description: Seroprotection rate was defined as the percentage of participants with anti-type 2-specific poliovirus neutralizing antibodies titers ≥ 1:8. Analysis Population Description: Participants in the per-protocol population previously vaccinated with OPV who received 2 doses of novel OPV2 (Groups 2 and 4).
    End point type
    Secondary
    End point timeframe
    Day 56
    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: The endpoint for the other arms is defined as a separate endpoint in the protocol and therefore also separated reported in the endpoint: Seroprotection Rate in Former IPV Recipients.
    End point values
    		 Group 2: OPV-vaccinated - Two doses of Novel OPV2 Candidate 1 Group 4: OPV-vaccinated - Two doses of Novel OPV2 Candidate 2
    Number of subjects analysed
    49
    49
    Units: percentage of participants
        number (confidence interval 95%)
    100 (93 to 100)
    100 (93 to 100)
    No statistical analyses for this end point

    Secondary: Seroprotection Rate in Former IPV Recipients

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    End point title
    		 Seroprotection Rate in Former IPV Recipients [6]
    End point description
    Measure Description: Seroprotection rate was defined as the percentage of participants with anti-type 2-specific poliovirus neutralizing antibodies titers ≥ 1:8. Analysis Population Description Participants in the per-protocol population previously vaccinated with IPV only. Samples for 2 participants in Group 5 on Day 0 were mixed up and are not included in the analysis
    End point type
    Secondary
    End point timeframe
    Day 0, Day 28, and Day 56
    Notes
    [6] - 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: The endpoint for the other arms is defined as a separate endpoint in the protocol and therefore also separated reported in the endpoint: Seroprotection Rate After Two Doses of Novel OPV2 in Former OPV Recipients.
    End point values
    		 Group 5: IPV-vaccinated - Two doses of Novel OPV2 Candidate 1 Group 6: IPV-vaccinated - Two doses of Novel OPV2 Candidate 2 Group 7: IPV-vaccinated - Two doses of placebo
    Number of subjects analysed
    17
    16
    16
    Units: percentage of participants
    number (confidence interval 95%)
        Day 0 (pre-vaccination)
    93 (68 to 100)
    94 (70 to 100)
    81 (54 to 96)
        Day 28
    100 (80 to 100)
    100 (79 to 100)
    75 (48 to 93)
        Day 56
    100 (80 to 100)
    100 (78 to 100)
    81 (54 to 96)
    No statistical analyses for this end point

    Secondary: Seroconversion Rate After a Single Dose of Novel OPV2 in Former OPV Recipients

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    End point title
    		 Seroconversion Rate After a Single Dose of Novel OPV2 in Former OPV Recipients
    End point description
    measure descripyion: Seroconversion is defined as a change from seronegative to seropositive (poliovirus type-2-specific neutralizing antibody titers ≥ 1:8), or for participants seropositive at Baseline, an antibody titer increase of ≥ 4-fold over Baseline titer. Analysis Population Description: Participants in the seroconversion subset of the per-protocol population previously vaccinated with OPV. The seroconversion subset included participants with Baseline titer sufficiently low to enable observation of a four-fold increase without breaching the ULOQ (ie, a titer ≤ 362). Since this endpoint was analyzed after 1 dose of nOPV, Groups 1 and 2 and Groups 3 and 4 are combined for analysis.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Group 1+2: OPV-vaccinated - novel OPV2 candidate 1 Group 3+4: OPV-vaccinated - novel OPV2 candidate 2
    Number of subjects analysed
    55
    47
    Units: percentage of participants
        number (confidence interval 95%)
    74.5 (61.0 to 85.3)
    51.1 (36.1 to 65.9)
    No statistical analyses for this end point

    Secondary: Seroconversion Rate After Two Doses of Novel OPV2 in Former OPV Recipients

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    End point title
    		 Seroconversion Rate After Two Doses of Novel OPV2 in Former OPV Recipients [7]
    End point description
    Measure description: Seroconversion is defined as a change from seronegative to seropositive (poliovirus type-2-specific neutralizing antibody titers ≥ 1:8), or for participants seropositive at Baseline, an antibody titer increase of ≥ 4-fold over Baseline titer. Analysis Population Description: Participants in the seroconversion subset of the per-protocol population previously vaccinated with OPV and who received 2 doses of novel OPV2 (Groups 2 and 4). The seroconversion subset included participants with Baseline titer sufficiently low to enable observation of a four-fold increase without breaching the ULOQ (ie, a titer ≤ 362).
    End point type
    Secondary
    End point timeframe
    Day 56
    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: The endpoint for the other arms is defined as a separate endpoint in the protocol and therefore also separated reported in the endpoint: Seroconversion Rate After Two Doses of Novel OPV2 in Former OPV Recipients.
    End point values
    		 Group 2: OPV-vaccinated - Two doses of Novel OPV2 Candidate 1 Group 4: OPV-vaccinated - Two doses of Novel OPV2 Candidate 2
    Number of subjects analysed
    27
    26
    Units: percentage of participants
        number (confidence interval 95%)
    74 (54 to 89)
    58 (37 to 77)
    No statistical analyses for this end point

    Secondary: Seroconversion Rate in Former IPV Recipients

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    End point title
    		 Seroconversion Rate in Former IPV Recipients [8]
    End point description
    Measure description: Seroconversion is defined as a change from seronegative to seropositive (poliovirus type-2-specific neutralizing antibody titers ≥ 1:8), or for participants seropositive at Baseline, a poliovirus type-2-specific neutralizing antibody titer increase of ≥ 4-fold over Baseline titer. Analysis Population Description Participants in the seroconversion subset of the per-protocol population previously vaccinated with IPV only. The seroconversion subset included participants with Baseline titer sufficiently low to enable observation of a four-fold increase without breaching the ULOQ (ie, a titer ≤ 362).
    End point type
    Secondary
    End point timeframe
    Day 28 and Day 56
    Notes
    [8] - 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: The endpoint for the other arms is defined as a separate endpoint in the protocol and therefore also separated reported in the endpoint: Seroconversion Rate After Two Doses of Novel OPV2 in Former OPV Recipients.
    End point values
    		 Group 5: IPV-vaccinated - Two doses of Novel OPV2 Candidate 1 Group 6: IPV-vaccinated - Two doses of Novel OPV2 Candidate 2 Group 7: IPV-vaccinated - Two doses of placebo
    Number of subjects analysed
    10
    12
    12
    Units: percentage of participants
    number (confidence interval 95%)
        Day 28
    100 (69 to 100)
    92 (62 to 100)
    0 (0 to 26)
        Day 56
    100 (69 to 100)
    82 (48 to 98)
    8 (0 to 38)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 42 days after each vaccination (42 days in Groups 1 and 3 and 70 days for all other Groups).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Group1: OPV-vaccinated - One dose of Novel OPV2 candidate 1
    Reporting group description
    		 Group1: OPV-vaccinated - One dose of Novel OPV2 candidate 1

    Reporting group title
    Group 2: OPV-vaccinated - two doses of novel OPV2 candidate 1
    Reporting group description
    		 Participants previously vaccinated with oral polio vaccine (OPV) received two doses of novel OPV2 candidate 1, 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total; approximately 10# 50% CCID50).

    Reporting group title
    Group 3: OPV-vaccinated - One dose of novel OPV2 candidate 2
    Reporting group description
    		 Participants previously vaccinated with OPV received one dose of novel OPV2 candidate 2 on study Day 0, administered orally as six drops (0.3 mL total; approximately 10# CCID50).

    Reporting group title
    Group 4: OPV-vaccinated - Two doses of novel OPV2 candidate 2
    Reporting group description
    		 Participants previously vaccinated OPV received two doses novel OPV2 candidate 2 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total; approximately 10# CCID50).

    Reporting group title
    Group 5: IPV-vaccinated - Two doses of novel OPV2 candidate 1
    Reporting group description
    		 Participants previously vaccinated with inactivated polio vaccine (IPV) received two doses of novel OPV2 candidate 1 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total; approximately 10# CCID50).

    Reporting group title
    Group 6: IPV-vaccinated - Two doses of novel OPV2 candidate 2
    Reporting group description
    		 Participants previously vaccinated with IPV received two doses of novel OPV2 candidate 2 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total; approximately 10# CCID50).

    Reporting group title
    Group 7: IPV-vaccinated - Two doses of placebo
    Reporting group description
    		 Participants previously vaccinated with IPV received two doses of placebo 28 days apart (Day 0 and Day 28), administered orally as six drops (0.3 mL total).

    Serious adverse events
    		 Group1: OPV-vaccinated - One dose of Novel OPV2 candidate 1 Group 2: OPV-vaccinated - two doses of novel OPV2 candidate 1 Group 3: OPV-vaccinated - One dose of novel OPV2 candidate 2 Group 4: OPV-vaccinated - Two doses of novel OPV2 candidate 2 Group 5: IPV-vaccinated - Two doses of novel OPV2 candidate 1 Group 6: IPV-vaccinated - Two doses of novel OPV2 candidate 2 Group 7: IPV-vaccinated - Two doses of placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Crohn's Disease
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group1: OPV-vaccinated - One dose of Novel OPV2 candidate 1 Group 2: OPV-vaccinated - two doses of novel OPV2 candidate 1 Group 3: OPV-vaccinated - One dose of novel OPV2 candidate 2 Group 4: OPV-vaccinated - Two doses of novel OPV2 candidate 2 Group 5: IPV-vaccinated - Two doses of novel OPV2 candidate 1 Group 6: IPV-vaccinated - Two doses of novel OPV2 candidate 2 Group 7: IPV-vaccinated - Two doses of placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 50 (88.00%)
    48 / 50 (96.00%)
    47 / 50 (94.00%)
    47 / 50 (94.00%)
    17 / 17 (100.00%)
    15 / 16 (93.75%)
    17 / 17 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    1
    Chills
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Crepitations
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Cyst
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 50 (6.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    3 / 16 (18.75%)
    3 / 17 (17.65%)
         occurrences all number
    1
    3
    2
    0
    0
    7
    6
    Feeling cold
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Feeling hot
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Hangover
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    Influenza like illness
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 50 (6.00%)
    4 / 50 (8.00%)
    1 / 50 (2.00%)
    1 / 17 (5.88%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    1
    3
    4
    1
    1
    1
    1
    Malaise
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Fungal infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    3
    0
    1
    2
    0
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    3 / 17 (17.65%)
         occurrences all number
    1
    3
    1
    2
    1
    0
    3
    Dyspnoea
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 50 (6.00%)
    3 / 50 (6.00%)
    3 / 50 (6.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    1
    3
    4
    4
    0
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    3 / 50 (6.00%)
    8 / 50 (16.00%)
    7 / 50 (14.00%)
    5 / 50 (10.00%)
    3 / 17 (17.65%)
    1 / 16 (6.25%)
    3 / 17 (17.65%)
         occurrences all number
    3
    12
    7
    5
    5
    1
    6
    Productive cough
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Sneezing
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Psychiatric disorders
    Burnout syndrome
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    1
    3
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    1
    Blood bilirubine
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 50 (6.00%)
    5 / 50 (10.00%)
    4 / 50 (8.00%)
    5 / 50 (10.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    7
    6
    5
    7
    1
    0
    2
    Blood immunoglobulin A decreased
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    1
    Blood potassium increased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    4 / 50 (8.00%)
    4 / 50 (8.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    4
    4
    0
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    1 / 17 (5.88%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    1
    1
    1
    1
    Eosinophil count increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    1 / 17 (5.88%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Lymphocyte percentage decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    0
    Platelet count increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Head injury
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Procedural nausea
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    Wrist fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    2 / 50 (4.00%)
    2 / 50 (4.00%)
    0 / 17 (0.00%)
    4 / 16 (25.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    5
    3
    2
    0
    4
    2
    Dysgeusia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Migraine
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    sleep deficit
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Tension headache
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Leucocytosis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    3 / 50 (6.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    3
    1
    0
    1
    0
    Leucopenia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Middle Ear Disorder
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Eye disorders
    Eye irritation
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 50 (6.00%)
    3 / 50 (6.00%)
    4 / 50 (8.00%)
    1 / 17 (5.88%)
    2 / 16 (12.50%)
    4 / 17 (23.53%)
         occurrences all number
    0
    4
    3
    5
    2
    2
    8
    Abdominal pain lower
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    3
    0
    0
    0
    Abnormal faeces
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    Cheilitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Constipation1
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    4 / 50 (8.00%)
    3 / 50 (6.00%)
    3 / 50 (6.00%)
    6 / 50 (12.00%)
    6 / 17 (35.29%)
    3 / 16 (18.75%)
    3 / 17 (17.65%)
         occurrences all number
    4
    7
    4
    10
    6
    10
    4
    Dyspepsia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    3 / 16 (18.75%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    3
    0
    Eructation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    4
    0
    Food poisoning
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    3 / 50 (6.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    Gastrointestinal sounds abnormal
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Gastrooesophageal reflux disease0
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Hyperaesthesia teeth
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 50 (6.00%)
    5 / 50 (10.00%)
    1 / 50 (2.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    3
    5
    1
    1
    0
    4
    Proctalgia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Rectal Tenesmus
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Swollen tongue
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Tongue discomfort
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    1 / 50 (2.00%)
    3 / 50 (6.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    1
    3
    0
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Eczema
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Night sweats
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    rash generalised
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Swelling face
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    arthralgia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    3 / 50 (6.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    0
    3
    0
    1
    0
    Arthritis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Back pain
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 50 (6.00%)
    3 / 50 (6.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    2 / 17 (11.76%)
         occurrences all number
    2
    4
    3
    1
    0
    2
    4
    Bursitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    musculoskeletal pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    1
    Myalgia
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 50 (4.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    2 / 16 (12.50%)
    3 / 17 (17.65%)
         occurrences all number
    5
    4
    4
    0
    1
    2
    8
    Neck pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    3 / 50 (6.00%)
    1 / 17 (5.88%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    3
    1
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    2 / 17 (11.76%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    0
    1
    2
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Ear lobe infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Enterobiasis
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    0
    1
    1
    0
    0
    Furuncle
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Herpes simplex
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 50 (8.00%)
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    5 / 17 (29.41%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    4
    4
    1
    2
    5
    1
    1
    Oral herpes
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Rash pustular
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 50 (6.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 17 (5.88%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
         occurrences all number
    0
    3
    0
    0
    1
    2
    0
    Sinusitis
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    2
    1
    1
    2
    0
    0
    0
    Tinea pedis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 50 (18.00%)
    4 / 50 (8.00%)
    7 / 50 (14.00%)
    13 / 50 (26.00%)
    0 / 17 (0.00%)
    5 / 16 (31.25%)
    9 / 17 (52.94%)
         occurrences all number
    13
    4
    8
    13
    0
    6
    10
    Urinary tract infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Viral rhinitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    1
    0
    0
    1
    1
    Hypophosphataemia
         subjects affected / exposed
    2 / 50 (4.00%)
    8 / 50 (16.00%)
    3 / 50 (6.00%)
    5 / 50 (10.00%)
    0 / 17 (0.00%)
    2 / 16 (12.50%)
    2 / 17 (11.76%)
         occurrences all number
    5
    12
    5
    6
    0
    3
    3
    headache
         subjects affected / exposed
    11 / 50 (22.00%)
    14 / 50 (28.00%)
    16 / 50 (32.00%)
    14 / 50 (28.00%)
    6 / 17 (35.29%)
    5 / 16 (31.25%)
    7 / 17 (41.18%)
         occurrences all number
    12
    24
    18
    18
    9
    10
    16

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Dec 2018
    In case of extended shedding of the subjects sampling of household contacts will be offered to the subjects’ households: this is explained in appendix 4 and also added at section 1.3.1 ‘Potential Risks’. Frequency of follow-up samples to be taken in case of extended shedding has been adapted: ‘every 3 weeks’ has been deleted and subjects will be asked to collect further 3 consecutive stool samples (with a maximum of one sample per day) after the last per-protocol sample as soon as these PCR-positive results are known (anticipated approximately 3 weeks after the last such sample provided for evaluation) and to repeat this until shedding is PCR-negative for type 2 poliovirus on 3 consecutive stool samples, which then determines study end for this person. This is adapted accordingly in the following sections: synopsis ‘Study/treatment duration’, section 9.1 ‘Study Completion’ and in Appendix 4. The DSMB will also monitor study enrollment, particularly for IPV-vaccinated subjects, and recommend truncation and/or closure of study groups if enrollment stagnates and when current enrollment is considered sufficient to meet study objectives and no safety signals occurred. The minimum number of IPV-vaccinated subjects agreed on by DSMB per candidate vaccine is 24. With a randomization of 2:1 for placebo the minimum study cohort size for Groups 5, 6 and 7 will be 16. In case of safety signals the DSMB reserves the right to reverse the truncated enrollment. This explanation is added in sections: Synopsis ‘Overview of Study Design’, section 4.1 ‘Overview of Study Design’ and section 6.6 ‘Randomization and Blinding’. Safety endpoint evaluation by age group for IPV- vaccinated subjects has been deleted in synopsis and section 3.1 ‘Primary endpoints’ and section 3.2 ‘Secondary endpoints’ Affiliation of statistician has been changed on signature page and section of Study Administrative Structure.

    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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