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    Clinical Trial Results:
    Immunogenicity and Safety of Sanofi Pasteur's DTaP-IPV-HB-PRP-T Combined Vaccine Given as a Primary Series and a Second Year of Life Booster in HIV-Exposed Infected and in HIV-Exposed Uninfected Infants in Republic of South Africa

    Summary
    EudraCT number
    		 2018-004708-21
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    13 Mar 2019

    Results information
    Results version number
    		 v1
    This version publication date
    28 Oct 2019
    First version publication date
    28 Oct 2019
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    A3L44
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02817451
    WHO universal trial number (UTN)
    		 U1111-1161-2610
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur
    Sponsor organisation address
    14 Espace Henry Vallée, Lyon, France, 69007
    Public contact
    Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - To evaluate the immunogenicity of the study vaccine 1 month after the 3-dose primary series in Human Immunodeficiency Virus (HIV)-exposed infected and in HIV-exposed uninfected infants. - To describe the persistence of all antibodies before receipt of the booster vaccination in HIV-exposed infected and in HIV-exposed uninfected infants. - To evaluate the immunogenicity of the study vaccine 1 month after the booster dose in HIV-exposed infected and in HIV-exposed uninfected infants.
    Protection of trial subjects
    Vaccinations were performed by qualified and trained study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After vaccination, subjects were also kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment was also available on site in case of any immediate allergic reactions.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Jul 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 64
    Worldwide total number of subjects
    64
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    64
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 1 centre in South Africa from 14 July 2016 to 13 March 2019.

    Pre-assignment
    Screening details
    		 A total of 64 subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled and vaccinated in the study.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HIV-Exposed Infected Subjects
    Arm description
    		 Subjects identified as polymerase chain reaction (PCR) positive for HIV received 3 doses of primary vaccination with Diphtheria (D), tetanus (T), pertussis (2-component acellular) (aP), recombinant Hepatitis B Hansenula polymorpha (Hep B) and inactivated poliovirus vaccine (IPV) adsorbed, and Haemophilus influenzae type b (Hib) (DTaP-IPV-HB-PRP-T) combined vaccine at 6, 10, and 14 weeks of age (Infant Series), followed by a booster dose approximately 12 months after the completion of the Infant Series (at 15 to 18 months of age).
    Arm type
    		 Experimental

    Investigational medicinal product name
    DTaP-IPV-HB-PRP-T combined vaccine
    Investigational medicinal product code
    Other name
    Hexaxim®
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL (millilitre), intramuscular injection into the anterolateral area of the right thigh.

    Arm title
    		 HIV-Exposed Uninfected Subjects
    Arm description
    		 Subjects identified as HIV-exposed during pregnancy but uninfected received 3 doses of primary vaccination with DTaP-IPV-HB-PRP-T combined vaccine at 6, 10, and 14 weeks of age (Infant Series), followed by a booster dose approximately 12 months after the completion of the Infant Series (at 15 to 18 months of age).
    Arm type
    		 Experimental

    Investigational medicinal product name
    DTaP-IPV-HB-PRP-T combined vaccine
    Investigational medicinal product code
    Other name
    Hexaxim®
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular injection into the anterolateral area of the right thigh.

    Number of subjects in period 1
    		HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Started
    14
    50
    Completed
    12
    40
    Not completed
    2
    10
         Consent withdrawn by subject
    1
    6
         Receipt of a vaccine unacceptable for use
    -
    1
         Lost to follow-up
    1
    -
         Non-compliance with the protocol
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HIV-Exposed Infected Subjects
    Reporting group description
    		 Subjects identified as polymerase chain reaction (PCR) positive for HIV received 3 doses of primary vaccination with Diphtheria (D), tetanus (T), pertussis (2-component acellular) (aP), recombinant Hepatitis B Hansenula polymorpha (Hep B) and inactivated poliovirus vaccine (IPV) adsorbed, and Haemophilus influenzae type b (Hib) (DTaP-IPV-HB-PRP-T) combined vaccine at 6, 10, and 14 weeks of age (Infant Series), followed by a booster dose approximately 12 months after the completion of the Infant Series (at 15 to 18 months of age).

    Reporting group title
    HIV-Exposed Uninfected Subjects
    Reporting group description
    		 Subjects identified as HIV-exposed during pregnancy but uninfected received 3 doses of primary vaccination with DTaP-IPV-HB-PRP-T combined vaccine at 6, 10, and 14 weeks of age (Infant Series), followed by a booster dose approximately 12 months after the completion of the Infant Series (at 15 to 18 months of age).

    Reporting group values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects Total
    Number of subjects
    		 14 50 64
    Age categorical
    Units: subjects
    Age continuous
    Units: weeks
        arithmetic mean (standard deviation)
    		 6.07 ( 0.267 ) 5.76 ( 0.431 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 29 38
        Male
    		 5 21 26

    End points

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    End points reporting groups
    Reporting group title
    HIV-Exposed Infected Subjects
    Reporting group description
    		 Subjects identified as polymerase chain reaction (PCR) positive for HIV received 3 doses of primary vaccination with Diphtheria (D), tetanus (T), pertussis (2-component acellular) (aP), recombinant Hepatitis B Hansenula polymorpha (Hep B) and inactivated poliovirus vaccine (IPV) adsorbed, and Haemophilus influenzae type b (Hib) (DTaP-IPV-HB-PRP-T) combined vaccine at 6, 10, and 14 weeks of age (Infant Series), followed by a booster dose approximately 12 months after the completion of the Infant Series (at 15 to 18 months of age).

    Reporting group title
    HIV-Exposed Uninfected Subjects
    Reporting group description
    		 Subjects identified as HIV-exposed during pregnancy but uninfected received 3 doses of primary vaccination with DTaP-IPV-HB-PRP-T combined vaccine at 6, 10, and 14 weeks of age (Infant Series), followed by a booster dose approximately 12 months after the completion of the Infant Series (at 15 to 18 months of age).

    Primary: Number of Subjects with Anti-Pertussis Toxoid (PT) and Anti-Filamentous Hemagglutinin (FHA) Antibody (Ab) Concentrations less than equal to (>=) Lower Limit of Quantification (LLOQ) and >=4*LLOQ at Baseline

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    End point title
    		 Number of Subjects with Anti-Pertussis Toxoid (PT) and Anti-Filamentous Hemagglutinin (FHA) Antibody (Ab) Concentrations less than equal to (>=) Lower Limit of Quantification (LLOQ) and >=4*LLOQ at Baseline [1]
    End point description
    Anti-PT and anti-FHA Ab concentrations were determined in terms of endotoxin units per millilitre (EU/mL). Analysis was performed on per-protocol analysis set which was a subset of the full analysis set (FAS) that included all subjects who had received at least one dose of study vaccine.
    End point type
    Primary
    End point timeframe
    Day 0 (baseline)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    8
    42
    Units: subjects
    number (not applicable)
        Anti-PT: >=LLOQ
    2
    23
        Anti-PT: >=4*LLOQ
    1
    6
        Anti-FHA: >=LLOQ
    6
    38
        Anti-FHA: >=4*LLOQ
    2
    23
    No statistical analyses for this end point

    Primary: Geometric Means of Anti-Pertussis Toxoid and Anti-Filamentous Hemagglutinin Antibody Concentrations at Baseline

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    End point title
    		 Geometric Means of Anti-Pertussis Toxoid and Anti-Filamentous Hemagglutinin Antibody Concentrations at Baseline [2]
    End point description
    Anti-PT and anti-FHA Ab levels were measured by enzyme-linked immunosorbent assay (ELISA) and anti-PT and anti-FHA Ab concentrations were determined in terms of EU/mL. Analysis was performed on per protocol analysis set.
    End point type
    Primary
    End point timeframe
    Day 0 (baseline)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    8
    42
    Units: EU/mL
    geometric mean (confidence interval 95%)
        Anti-PT
    1.55 (0.774 to 3.10)
    2.83 (1.95 to 4.11)
        Anti-FHA
    3.82 (1.46 to 9.98)
    9.62 (6.38 to 14.5)
    No statistical analyses for this end point

    Primary: Geometric Means of Antibody Titers/Concentrations After Primary Series Vaccination

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    End point title
    		 Geometric Means of Antibody Titers/Concentrations After Primary Series Vaccination [3]
    End point description
    Anti-diphtheria Ab levels were measured by a toxin neutralisation test. Anti-tetanus, anti-PT and anti-FHA Ab levels were measured by ELISA. Anti-poliovirus types 1, 2, and 3 Ab levels were measured by neutralisation assay. Anti-Hep B Ab levels were measured by VITROS ECi/ECiQ Immunodiagnostic system using chemiluminescence detection technology. Anti-polyribosylribitol phosphate (PRP) Ab levels were measured using a Farr-type radioimmunoassay (RIA). Ab concentrations were determined as: anti-diphtheria >=0.01 international units (IU)/mL, >=0.1 IU/mL, 1.0 IU/mL, anti-tetanus >=0.01 IU/mL, >=0.1 IU/mL, and >=1.0 IU/mL, anti-PT and anti-FHA EU/mL, anti-PRP >=0.15 microgram (mcg)/mL, >=1.0 mcg/mL, anti-Poliovirus types 1, 2, and 3 Ab titers >=8 (1/dilution [dil]), Anti-Hep B >=10 milli (m) IU/mL, and >=100 mIU/mL. Analysis was performed on per-protocol analysis set. Here, ‘n’ signifies subjects with available data for each specified category.
    End point type
    Primary
    End point timeframe
    Day 90 (1 month after third dose)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    8
    42
    Units: titers
    geometric mean (confidence interval 95%)
        Anti-Diphtheria; (IU/mL) (n= 8,42)
    4.72 (3.42 to 6.53)
    2.78 (2.40 to 3.22)
        Anti-Tetanus; (IU/mL) (n= 8,42)
    4.81 (2.89 to 8.01)
    1.37 (1.04 to 1.80)
        Anti-PT; (EU/mL) (n= 8,42)
    287 (181 to 457)
    151 (128 to 178)
        Anti-FHA; (EU/mL) (n= 8,42)
    618 (303 to 1261)
    315 (261 to 379)
        Anti-Polio 1; (1/dil) (n= 8,41)
    3298 (1476 to 7369)
    1523 (1139 to 2038)
        Anti-Polio 2; (1/dil) (n= 8,41)
    3756 (1569 to 8989)
    1365 (1009 to 1847)
        Anti-Polio 3; (1/dil) (n= 8,40)
    4096 (1918 to 8747)
    2253 (1647 to 3082)
        Anti-Hep B; (mIU/mL) (n= 8,42)
    615 (212 to 1783)
    244 (174 to 342)
        Anti-PRP; (mcg/mL) (n= 8,41)
    3.72 (1.15 to 12.0)
    2.48 (1.61 to 3.81)
    No statistical analyses for this end point

    Primary: Number of Subjects With Seroprotection After Primary Series Vaccination

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    End point title
    		 Number of Subjects With Seroprotection After Primary Series Vaccination [4]
    End point description
    Seroprotection was determined as: anti-diptheria Ab concentrations >=0.01 IU/mL, >=0.1 IU/mL, and >=1.0 IU/mL, anti-tetanus Ab concentrations >=0.01 IU/mL, >=0.1 IU/mL, and >=1.0 IU/mL, anti-PT and anti-FHA Ab concentrations EU/mL (>=LLOQ and >=4*LLOQ), anti-PRP Ab concentrations >=0.15 mcg/mL and >=1.0 mcg/mL, anti-poliovirus 1, 2, and 3 Ab titers >=8 (1/dil), anti-Hep B Ab concentrations >=10 mIU/mL and >=100 mIU/mL. Analysis was performed on per-protocol analysis set. Here, ‘n’ signifies subjects with available data for each specified category.
    End point type
    Primary
    End point timeframe
    Day 90 (1 month after third dose)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    8
    42
    Units: subjects
    number (not applicable)
        Anti-Diphtheria; (>=0.01 IU/mL) (n=8,42)
    8
    42
        Anti-Diphtheria; (>=0.1 IU/mL) (n=8,42)
    8
    42
        Anti-Diphtheria; (>=1.0 IU/mL) (n=8,42)
    8
    41
        Anti-Tetanus; (>=0.01 IU/mL) (n=8,42)
    8
    42
        Anti-Tetanus; (>=0.1 IU/mL) (n=8,42)
    8
    42
        Anti-Tetanus; (>=1.0 IU/mL) (n=8,42)
    8
    29
        Anti-PT; (EU/mL, >=LLOQ) (n= 8,42)
    8
    42
        Anti-PT; (EU/mL, >=4*LLOQ) (n= 8,42)
    8
    42
        Anti-FHA; (EU/mL, >=LLOQ) (n= 8,42)
    8
    42
        Anti-FHA; (EU/mL, >=4*LLOQ) (n= 8,42)
    8
    42
        Anti-Polio 1; (>=8 [1/dil]) (n= 8,41)
    8
    41
        Anti-Polio 2; (>=8 [1/dil]) (n= 8,41)
    8
    41
        Anti-Polio 3; (>=8 [1/dil]) (n= 8,40)
    8
    40
        Anti-Hep B; (>=10 mIU/mL) (n= 8,42)
    8
    42
        Anti-Hep B; (>=100 mIU/mL) (n= 8,42)
    7
    35
        Anti-PRP; (>=0.15 mcg/mL) (n= 8,41)
    8
    40
        Anti-PRP; (>=1.0 mcg/mL) (n= 8,41)
    7
    30
    No statistical analyses for this end point

    Primary: Number of Subjects with Vaccine Response or Seroconversion After Primary Series Vaccination

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    End point title
    		 Number of Subjects with Vaccine Response or Seroconversion After Primary Series Vaccination [5]
    End point description
    Vaccine response was defined for anti-PT and anti-FHA as Ab post-Dose 3 concentrations >=4*LLOQ, if pre-Dose (Day 0) Ab concentration is <4*LLOQ or 1 month after third dose (Day 90) concentrations >= pre-Dose Ab concentrations if pre-Dose (Day 0) concentrations >=4*LLOQ. Seroconversion for anti-PT and anti-FHA was defined as >=4-fold Ab concentrations increase from pre-Dose (Day 0) to 1 month after third dose (Day 90). Analysis was performed on per-protocol analysis set.
    End point type
    Primary
    End point timeframe
    Day 0 (baseline), Day 90 (1 month after third dose)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    8
    42
    Units: subjects
    number (not applicable)
        Anti-PT; Day 90/ Day 0 (Vaccine Response)
    8
    42
        Anti-PT; Day 90/Day 0 (Seroconversion)
    8
    38
        Anti-FHA; Day 90/Day 0 (Vaccine Response)
    8
    42
        Anti-FHA; Day 90/Day 0 (Seroconversion)
    8
    37
    No statistical analyses for this end point

    Primary: Geometric Means of Antibody Titers/Concentrations After Booster Vaccination

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    End point title
    		 Geometric Means of Antibody Titers/Concentrations After Booster Vaccination [6]
    End point description
    Anti-diphtheria Ab levels were measured by toxin neutralisation test. Anti-tetanus, anti-PT, and anti-FHA Ab levels were measured by ELISA. Anti-poliovirus types 1, 2, and 3 Ab levels were measured by neutralisation assay. Anti-Hep B Ab levels were measured by VITROS ECi/ECiQ Immunodiagnostic system using chemiluminescence detection technology. Anti-PRP Ab levels were measured using a Farr-type RIA. Ab concentrations: anti-diphtheria >=0.01 IU/mL, >=0.1 IU/mL, >=1.0 IU/mL, anti-tetanus >=0.01 IU/mL, >=0.1 IU/mL, and >=1.0 IU/mL, anti-PT and anti-FHA EU/mL, anti-PRP >=0.15 mcg/mL, >=1.0 mcg/mL, anti-poliovirus 1, 2, and 3 Ab titers >=8 (1/dil), anti-Hep B >=10 mIU/mL, and >=100 mIU/mL. Analysis was performed on booster per-protocol analysis set which included subjects who received the booster dose of the vaccine, and with at least one antibody titer available pre-booster dose or one month post-booster.
    End point type
    Primary
    End point timeframe
    Day 420 (1 month after booster vaccination)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    7
    29
    Units: titers
    geometric mean (confidence interval 95%)
        Anti-Diphtheria; (IU/mL)
    9.72 (4.59 to 20.6)
    6.20 (4.86 to 7.92)
        Anti-Tetanus; (IU/mL)
    13.0 (7.11 to 23.9)
    5.90 (4.30 to 8.10)
        Anti-PT; (EU/mL)
    310 (165 to 582)
    194 (149 to 252)
        Anti-FHA; (EU/mL)
    369 (187 to 726)
    229 (162 to 324)
        Anti-Polio 1; (1/dil)
    3710 (944 to 14583)
    3999 (2848 to 5617)
        Anti-Polio 2; (1/dil)
    7420 (2153 to 25574)
    7445 (5361 to 10340)
        Anti-Polio 3; (1/dil)
    5247 (1543 to 17834)
    6450 (4207 to 9889)
        Anti-Hep B; (mIU/mL)
    2371 (394 to 14286)
    2014 (945 to 4292)
        Anti-PRP; (mcg/mL)
    40.1 (8.71 to 184)
    39.8 (20.8 to 76.3)
    No statistical analyses for this end point

    Primary: Number of Subjects With Seroprotection After Booster Vaccination

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    End point title
    		 Number of Subjects With Seroprotection After Booster Vaccination [7]
    End point description
    Seroprotection: anti-diphtheria Ab concentrations >=0.01 IU/mL, >=0.1 IU/mL, and >=1.0 IU/mL, anti-tetanus Ab concentrations >=0.01 IU/mL, >=0.1 IU/mL, and >=1.0 IU/mL, anti-PT and anti-FHA Ab concentrations EU/mL (>=LLOQ and >=4*LLOQ), anti-PRP Ab concentrations >=0.15 mcg/mL and >=1.0 mcg/mL, anti-poliovirus 1, 2, and 3 Ab titers >=8 (1/dil), and anti-Hep B Ab concentrations >=10 mIU/mL and >=100 mIU/mL. Analysis was performed on booster per-protocol analysis Set.
    End point type
    Primary
    End point timeframe
    Day 420 (1 month after booster vaccination)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    7
    29
    Units: subjects
    number (not applicable)
        Anti-Diphtheria; (>=0.01 IU/mL)
    7
    29
        Anti-Diphtheria; (>=0.1 IU/mL)
    7
    29
        Anti-Diphtheria; (>=1.0 IU/mL)
    7
    29
        Anti-Tetanus; (>=0.01 IU/mL)
    7
    29
        Anti-Tetanus; (>=0.1 IU/mL)
    7
    29
        Anti-Tetanus; (>=1.0 IU/mL)
    7
    28
        Anti-PT; (EU/mL, >=LLOQ)
    7
    29
        Anti-PT; (EU/mL, >=4*LLOQ)
    7
    29
        Anti-FHA; (EU/mL, >=LLOQ)
    7
    29
        Anti-FHA; (EU/mL, >=4*LLOQ)
    7
    29
        Anti-Polio 1; (>=8 [1/dil])
    7
    29
        Anti-Polio 2; (>=8 [1/dil])
    7
    29
        Anti-Polio 3; (>=8 [1/dil])
    7
    29
        Anti-Hep B; (>=10 mIU/mL)
    7
    29
        Anti-Hep B; (>=100 mIU/mL)
    7
    26
        Anti-PRP; (>=0.15 mcg/mL)
    7
    29
        Anti-PRP; (>=1.0 mcg/mL)
    7
    28
    No statistical analyses for this end point

    Primary: Number of Subjects With Vaccine Response or Seroconversion After Booster Vaccination

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    End point title
    		 Number of Subjects With Vaccine Response or Seroconversion After Booster Vaccination [8]
    End point description
    Vaccine response was defined for anti-PT and anti-FHA as >=4 fold Ab concentrations increase from pre-dose (Day 0) to 1 month after booster dose (Day 420), if pre-Dose (Day 0) Ab concentrations <4*LLOQ; or >=2 fold Ab concentrations increase from pre- dose (Day 0) to 1 month after booster dose (Day 420), if pre-dose (Day 0) Ab concentrations >=4*LLOQ. Seroconversion was defined for anti-PT and anti-FHA as >=4 fold Ab concentrations increase from pre-dose (Day 0) to 1 month after booster dose. Analysis was performed on booster per-protocol analysis set.
    End point type
    Primary
    End point timeframe
    Day 0 (baseline), Day 420 (1 month after booster vaccination)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    7
    29
    Units: subjects
    number (not applicable)
        Anti-PT; Day 420/Day 0 (Vaccine Response)
    7
    29
        Anti-PT; Day 420/Day 0 (Seroconversion)
    7
    28
        Anti-FHA; Day 420/Day 0 (Vaccine Response)
    7
    28
        Anti-FHA; Day 420/Day 0 (Seroconversion)
    7
    26
    No statistical analyses for this end point

    Primary: Number of Subjects With Booster Response After Booster Vaccination

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    End point title
    		 Number of Subjects With Booster Response After Booster Vaccination [9]
    End point description
    Booster response was defined for anti-PT and anti-FHA as >=4 fold Ab concentrations increase from pre-booster (Day 390) to 1 month after booster dose (Day 420), if pre-booster Ab concentrations <4*LLOQ; or >=2 fold Ab concentrations increase from pre-booster (Day 390) to 1 month after booster dose (Day 390) if pre-Booster Ab concentrations >=4*LLOQ. Analysis was performed on booster per-protocol analysis set.
    End point type
    Primary
    End point timeframe
    Day 390 (pre-booster), Day 420 (1 month after booster dose)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    7
    29
    Units: subjects
    number (not applicable)
        Anti-PT; Day 420/Day 390 (Booster Response)
    7
    29
        Anti-FHA; Day 420/Day 390 (Booster Response)
    6
    27
    No statistical analyses for this end point

    Secondary: Number of Subjects With Immediate Unsolicited Adverse Events (AE) After Primary Series Vaccination

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    End point title
    		 Number of Subjects With Immediate Unsolicited Adverse Events (AE) After Primary Series Vaccination
    End point description
    An unsolicited AE is an observed AE that does not fulfill the conditions prelisted in the electronic case report form (eCRF) in terms of diagnosis and/or onset post-vaccination. Analysis was performed on safety analysis set which included subjects who had received at least one dose of study vaccine.
    End point type
    Secondary
    End point timeframe
    Within 30 minutes after vaccination
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    14
    49
    Units: subjects
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Solicited Injections Site or Systemic Reactions After Primary Series Vaccination

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    End point title
    		 Number of Subjects With Solicited Injections Site or Systemic Reactions After Primary Series Vaccination
    End point description
    A solicited reaction is an adverse reaction observed and reported under the conditions (symptom and onset) prelisted (i.e., solicited) in the eCRF and considered as related to vaccination. Solicited injection site reactions: injection site tenderness, erythema, and swelling. Solicited systemic reactions: fever, vomiting, crying abnormal, drowsiness, appetite lost, and irritability. Analysis was performed on safety analysis set. Here, number of subjects analysed signifies subjects evaluable for this end-point.
    End point type
    Secondary
    End point timeframe
    Within 7 days after vaccination
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    14
    48
    Units: subjects
    number (not applicable)
        Injection site tenderness
    4
    27
        Injection site erythema
    0
    2
        Injection site swelling
    0
    5
        Fever
    2
    3
        Vomiting
    3
    13
        Crying abnormal
    7
    30
        Drowsiness
    4
    19
        Appetite lost
    6
    10
        Irritability
    5
    24
    No statistical analyses for this end point

    Secondary: Number of Subjects With Unsolicited Adverse Events After Primary Series Vaccination

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    End point title
    		 Number of Subjects With Unsolicited Adverse Events After Primary Series Vaccination
    End point description
    An unsolicited AE is an observed AE that does not fulfill the conditions prelisted in the eCRF in terms of diagnosis and/or onset post-vaccination. An unsolicited non-serious AE is an unsolicited AE excluding serious adverse events (SAEs). Systemic AEs are all AEs that are not injection site reactions. They therefore include systemic manifestations such as headache, fever, as well as localized or topical manifestations that are not associated with the vaccination site. Analysis was performed on safety analysis set.
    End point type
    Secondary
    End point timeframe
    Within 30 days after vaccination
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    14
    49
    Units: subjects
    number (not applicable)
        Unsolicited AE
    7
    29
        Unsolicited non-serious AE
    6
    29
        Unsolicited non-serious systemic AE
    6
    29
    No statistical analyses for this end point

    Secondary: Number of Subjects With Serious Adverse Events During the Study

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    End point title
    		 Number of Subjects With Serious Adverse Events During the Study
    End point description
    An SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is an important medical event. Analysis was performed on safety analysis set.
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 420
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    14
    49
    Units: subjects
        number (not applicable)
    5
    4
    No statistical analyses for this end point

    Secondary: Number of Subjects With Immediate Unsolicited Adverse Events After Booster Vaccination

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    End point title
    		 Number of Subjects With Immediate Unsolicited Adverse Events After Booster Vaccination
    End point description
    An unsolicited AE is an observed AE that does not fulfill the conditions prelisted in the eCRF in terms of diagnosis and/or onset post-vaccination. Analysis was performed on booster safety analysis set which included the subjects who had received the booster dose of study vaccine.
    End point type
    Secondary
    End point timeframe
    Within 30 minutes after booster vaccination
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    12
    40
    Units: subjects
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Solicited Injection Site or Systemic Reactions After Booster Vaccination

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    End point title
    		 Number of Subjects With Solicited Injection Site or Systemic Reactions After Booster Vaccination
    End point description
    A solicited reaction is an adverse reaction observed and reported under the conditions (symptom and onset) prelisted (i.e., solicited) in the eCRF and considered as related to vaccination. Solicited injection site reactions: tenderness, erythema, swelling, and extensive limb swelling. Solicited systemic reactions: fever, vomiting, crying abnormal, drowsiness, appetite lost, and irritability. Analysis was performed on booster safety analysis set.
    End point type
    Secondary
    End point timeframe
    Within 7 days after booster vaccination
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    12
    40
    Units: subjects
    number (not applicable)
        Injection site tenderness
    4
    14
        Injection site erythema
    0
    1
        Injection site swelling
    1
    0
        Extensive swelling of vaccinated limb
    0
    0
        Fever
    3
    1
        Vomiting
    2
    1
        Crying abnormal
    5
    12
        Drowsiness
    0
    7
        Appetite lost
    4
    11
        Irritability
    3
    10
    No statistical analyses for this end point

    Secondary: Number of Subjects With Unsolicited Adverse Events After Booster Vaccination

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    End point title
    		 Number of Subjects With Unsolicited Adverse Events After Booster Vaccination
    End point description
    An unsolicited AE is an observed AE that does not fulfill the conditions prelisted in the eCRF in terms of diagnosis and/or onset post-vaccination. An unsolicited non-serious AE is an unsolicited AE excluding SAEs. Systemic AEs are all AEs that are not injection site reactions. They therefore include systemic manifestations such as headache, fever, as well as localized or topical manifestations that are not associated with the vaccination site. Analysis was performed on booster safety analysis set.
    End point type
    Secondary
    End point timeframe
    Within 30 days after booster vaccination
    End point values
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Number of subjects analysed
    12
    40
    Units: subjects
    number (not applicable)
        Unsolicited AE
    0
    10
        Unsolicited non-serious AE
    0
    10
        Unsolicited non-serious systemic AE
    0
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited reactions (SR): collected up to Day 7 after each vaccination, non-serious unsolicited adverse events were collected up to Day 30 after each vaccination. SAEs: throughout the trial (up to 30 days after primary series and booster vaccination).
    Adverse event reporting additional description
    SR: AE prelisted in eCRF, considered related to vaccination. SR was therefore, an adverse drug reaction observed, reported under conditions (symptom and onset) prelisted in eCRF. Unsolicited AE: an observed AE that does not fulfill conditions prelisted in eCRF in terms of diagnosis and/or onset post-vaccination. Analysis done on safety analysis set
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    HIV-Exposed Infected Subjects
    Reporting group description
    		 Subjects identified as PCR positive for HIV received 3 doses of primary vaccination with DTaP-IPV-HB-PRP-T combined vaccine at 6, 10 and 14 weeks of age (Infant Series), followed by a booster dose approximately 12 months after the completion of the Infant Series (at 15 to 18 months of age).

    Reporting group title
    HIV-Exposed Uninfected Subjects
    Reporting group description
    		 Subjects identified as HIV-exposed during pregnancy but uninfected received 3 doses of primary vaccination with DTaP-IPV-HB-PRP-T combined vaccine at 6, 10 and 14 weeks of age (Infant Series), followed by a booster dose approximately 12 months after the completion of the Infant Series (at 15 to 18 months of age).

    Serious adverse events
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 14 (35.71%)
    4 / 49 (8.16%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    Abscess Limb
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain Abscess
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup Infectious
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis Jirovecii Pneumonia
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Malnutrition
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 HIV-Exposed Infected Subjects HIV-Exposed Uninfected Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 14 (85.71%)
    46 / 49 (93.88%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    4 / 14 (28.57%)
    22 / 49 (44.90%)
         occurrences all number
    43
    61
    General disorders and administration site conditions
    Crying
         subjects affected / exposed
    8 / 14 (57.14%)
    34 / 49 (69.39%)
         occurrences all number
    67
    139
    Injection Site Pain
         subjects affected / exposed
    5 / 14 (35.71%)
    30 / 49 (61.22%)
         occurrences all number
    54
    127
    Injection Site Swelling
         subjects affected / exposed
    1 / 14 (7.14%)
    5 / 49 (10.20%)
         occurrences all number
    8
    21
    Pyrexia
         subjects affected / exposed
    5 / 14 (35.71%)
    4 / 49 (8.16%)
         occurrences all number
    10
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 49 (2.04%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed
    4 / 14 (28.57%)
    13 / 49 (26.53%)
         occurrences all number
    20
    37
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 14 (7.14%)
    6 / 49 (12.24%)
         occurrences all number
    2
    7
    Nasal Congestion
         subjects affected / exposed
    1 / 14 (7.14%)
    10 / 49 (20.41%)
         occurrences all number
    1
    11
    Skin and subcutaneous tissue disorders
    Dermatitis Diaper
         subjects affected / exposed
    0 / 14 (0.00%)
    3 / 49 (6.12%)
         occurrences all number
    0
    4
    Rash
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 49 (4.08%)
         occurrences all number
    1
    2
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    6 / 14 (42.86%)
    26 / 49 (53.06%)
         occurrences all number
    54
    96
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 14 (0.00%)
    3 / 49 (6.12%)
         occurrences all number
    0
    3
    Fungal Skin Infection
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 49 (4.08%)
         occurrences all number
    2
    2
    Gastroenteritis
         subjects affected / exposed
    1 / 14 (7.14%)
    3 / 49 (6.12%)
         occurrences all number
    1
    3
    Oral Candidiasis
         subjects affected / exposed
    1 / 14 (7.14%)
    5 / 49 (10.20%)
         occurrences all number
    1
    5
    Upper Respiratory Tract Infection
         subjects affected / exposed
    3 / 14 (21.43%)
    17 / 49 (34.69%)
         occurrences all number
    3
    19
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    7 / 14 (50.00%)
    16 / 49 (32.65%)
         occurrences all number
    63
    63

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Dec 2015
    Following amendment changes were made: the table of procedures were edited to more accurately represent the intentions found in the protocol, the schedule of visits was edited to more accurately represent the procedures to be followed at each visit, in Section 6.5 of the protocol, information was added to more clearly describe the process of screening subjects in this study, the tympanic route temperature was replaced by the axillary route temperature to be used in this study for determining temperature. Note that the oral route could also be used.
    12 Feb 2016
    Following amendment changes were made: the exclusion criterion #7 was modified: the temperature was >=38.0 degree Celsius (°C) in lieu of >=37.4°C; the table of procedures was updated as follows: during the screening period, the demographic data of all the subjects were to be collected in the CRF, at Visit 1 (Day 0), the vaccination history of all the subjects’ mother was to be collected in the CRF, memory aid checked – Visit 5 was added with a cross checked at Visit 5 (Day 390), Visit 5 (booster vaccine injection) was mentioned according to Visit 3 (last vaccine injection), section 5.1.4 visit procedures of the protocol was updated according to the table of procedures.
    20 Oct 2016
    Following amendment changes were made: the period of detection was extended to 6 weeks of age in lieu of 4 to 6 weeks of age, subject’s inclusion was modified, infants detected HIV+ outside the study screening process could be included, the screening criterion #2 was modified: self-reported or maternity-reported of HIV infection in the mother, not only documented proof HIV infection in the mother, the inclusion #1 and #3 were modified: infants born to an adult mother and aged 35 to 56 days (not 49 days) (between 5 and 8 weeks (not 7 weeks) of age) on the day of inclusion and born with a birth weight >=2.0 kg (not 2.5 kg), the table of procedure was updated according to the extension of the screening phase and the subject’s age at inclusion (inclusion criterion #1), the number of countries, where the product has been licensed, was modified: 104 countries in lieu of 78 countries, the visit procedures was updated according to the additional way of selection of subjects.

    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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