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    Clinical Trial Results:
    A phase III, randomized, open, controlled study to assess the immunogenicity, safety and reactogenicity of GlaxoSmithKline (GSK) Biologicals’ 10-valent pneumococcal conjugate vaccine as a 3-dose primary immunization course at 6, 10 and 14 weeks of age in Sub-Saharan Africa, co-administered with GSK Biologicals’ DTPw-HBV/Hib and OPV vaccines.

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2011-004650-25
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    10 Dec 2009

    Results information
    Results version number
    		 v2
    This version publication date
    07 Apr 2016
    First version publication date
    05 Jul 2015
    Other versions
    		 v1 (removed from public view) , v3
    Version creation reason
    • Correction of full data set
    Data correction due to a system error in EudraCT – Results: categories issue. A few data (typos) were corrected in some endpoints.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    110521
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00678301
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l’Institut 89, Rixensart, Belgium, B-1330
    Public contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.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 Oct 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the immunogenicity of GSK Biologicals’ 10-valent pneumococcal conjugate vaccine in Sub-Saharan Africa, one month post dose 3.
    Protection of trial subjects
    All subjects were supervised closely for at least 30 minutes following vaccination with appropriate medical treatment readily available. Vaccines were administered by qualified and trained personnel. Vaccines were administered only to eligible subjects that had no contraindications to any components of the vaccines. Subjects were followed up from the time the subject consented to participate in the study through consent by his/her parents/guardians until she/he was discharged.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jun 2008
    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
    Nigeria: 127
    Country: Number of subjects enrolled
    Mali: 238
    Worldwide total number of subjects
    365
    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)
    365
    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
    		 -

    Pre-assignment
    Screening details
    		 At screening, the following steps occurred: check for inclusion/exclusion criteria, contraindications/precautions, medical and vaccination history of the subjects and signing or thumb-printing informed consent forms.

    Pre-assignment period milestones
    Number of subjects started
    		 365
    Number of subjects completed
    		 357

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Subject not vaccinated: 8
    Period 1
    Period 1 title
    Entire Study period (Months 0-3) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 10Pn-PD-DiT/EPI Group
    Arm description
    		 Subjects in this group received 3 doses of 10Pn-PD-DiT vaccine, GSK Biologicals’ 10-valent pneumococcal conjugate 1024850A vaccine (later marketed as Synflorix) according to a 3-dose schedule at 6-10-14 weeks of age co-administered with 3 doses of Expanded Program on Immunization (EPI) vaccines Zilbrix™ Hib (or DTPw-HBV/Hib) and Polio Sabin™ (or OPV) according to the same schedule. The 10Pn-PD-DiT and DTPw-HBV/Hib vaccines were administered by intramuscular injection, in the right and left thigh respectively. The OPV vaccine was administered orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    10-valent streptococcus pneumoniae conjugate vaccine
    Investigational medicinal product code
    10Pn-PD-DiT
    Other name
    10Pn, 10Pn-PD-DiT, GSK1024850A, Synflorix
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The 10Pn-PD-DiT vaccine was administered by intramuscular injection, in the right thigh, according to a 3-dose schedule at 6-10-14 weeks of age.

    Investigational medicinal product name
    Polio Sabin
    Investigational medicinal product code
    Other name
    OPV
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The OPV vaccine was administered orally, according to a 3-dose schedule at 6-10-14 weeks of age.

    Investigational medicinal product name
    Zilbrix Hib
    Investigational medicinal product code
    Other name
    DTPw-HBV/Hib
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The DTPw-HBV/Hib vaccine was administered by intramuscular injection, in the left thigh, according to a 3-dose schedule at 6-10-14 weeks of age.

    Arm title
    		 EPI Group
    Arm description
    		 Subjects in this group received 3 doses of Expanded Program on Immunization (EPI) vaccines Zilbrix™ Hib (or DTPw-HBV/Hib) and Polio Sabin™ (or OPV) according to a 3-dose schedule at 6-10-14 weeks of age. The DTPw-HBV/Hib vaccine was administered by intramuscular injection, in the left thigh. The OPV vaccine was administered orally.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Polio Sabin
    Investigational medicinal product code
    Other name
    OPV
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The OPV vaccine was administered orally, according to a 3-dose schedule at 6-10-14 weeks of age.

    Investigational medicinal product name
    Zilbrix Hib
    Investigational medicinal product code
    Other name
    DTPw-HBV/Hib
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The DTPw-HBV/Hib vaccine was administered by intramuscular injection, in the left thigh, according to a 3-dose schedule at 6-10-14 weeks of age.

    Number of subjects in period 1 [1]
    		10Pn-PD-DiT/EPI Group EPI Group
    Started
    239
    118
    Completed
    231
    116
    Not completed
    8
    2
         Consent withdrawn by subject
    4
    -
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    3
    1
         Non-compliance with study procedures
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 365 subjects were enrolled but 8 subjects didn't received vaccination.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    10Pn-PD-DiT/EPI Group
    Reporting group description
    		 Subjects in this group received 3 doses of 10Pn-PD-DiT vaccine, GSK Biologicals’ 10-valent pneumococcal conjugate 1024850A vaccine (later marketed as Synflorix) according to a 3-dose schedule at 6-10-14 weeks of age co-administered with 3 doses of Expanded Program on Immunization (EPI) vaccines Zilbrix™ Hib (or DTPw-HBV/Hib) and Polio Sabin™ (or OPV) according to the same schedule. The 10Pn-PD-DiT and DTPw-HBV/Hib vaccines were administered by intramuscular injection, in the right and left thigh respectively. The OPV vaccine was administered orally.

    Reporting group title
    EPI Group
    Reporting group description
    		 Subjects in this group received 3 doses of Expanded Program on Immunization (EPI) vaccines Zilbrix™ Hib (or DTPw-HBV/Hib) and Polio Sabin™ (or OPV) according to a 3-dose schedule at 6-10-14 weeks of age. The DTPw-HBV/Hib vaccine was administered by intramuscular injection, in the left thigh. The OPV vaccine was administered orally.

    Reporting group values
    		 10Pn-PD-DiT/EPI Group EPI Group Total
    Number of subjects
    		 239 118 357
    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: weeks
        arithmetic mean (standard deviation)
    		 7.1 ( 1.15 ) 7 ( 1.18 ) -
    Gender categorical
    Units: Subjects
        Female
    		 119 62 181
        Male
    		 120 56 176

    End points

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    End points reporting groups
    Reporting group title
    10Pn-PD-DiT/EPI Group
    Reporting group description
    		 Subjects in this group received 3 doses of 10Pn-PD-DiT vaccine, GSK Biologicals’ 10-valent pneumococcal conjugate 1024850A vaccine (later marketed as Synflorix) according to a 3-dose schedule at 6-10-14 weeks of age co-administered with 3 doses of Expanded Program on Immunization (EPI) vaccines Zilbrix™ Hib (or DTPw-HBV/Hib) and Polio Sabin™ (or OPV) according to the same schedule. The 10Pn-PD-DiT and DTPw-HBV/Hib vaccines were administered by intramuscular injection, in the right and left thigh respectively. The OPV vaccine was administered orally.

    Reporting group title
    EPI Group
    Reporting group description
    		 Subjects in this group received 3 doses of Expanded Program on Immunization (EPI) vaccines Zilbrix™ Hib (or DTPw-HBV/Hib) and Polio Sabin™ (or OPV) according to a 3-dose schedule at 6-10-14 weeks of age. The DTPw-HBV/Hib vaccine was administered by intramuscular injection, in the left thigh. The OPV vaccine was administered orally.

    Primary: Concentrations of antibodies against vaccine pneumococcal serotypes

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    End point title
    		 Concentrations of antibodies against vaccine pneumococcal serotypes [1]
    End point description
    Pneumococcal serotypes assessed were vaccine pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. Seropositivity cut-off for the assay was an anti-pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F antibody (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) concentrations >= 0.05 microgram per milliliter (µg/mL).
    End point type
    Primary
    End point timeframe
    At Month 3, one month after the administration of the third dose of 10Pn-PD-DiT vaccine
    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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    217
    112
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-1 [N=217;108]
    2.69 (2.42 to 2.99)
    0.03 (0.03 to 0.03)
        Anti-4 [N=217;112]
    3.44 (3.06 to 3.87)
    0.03 (0.03 to 0.03)
        Anti-5 [N=217;109]
    4.17 (3.75 to 4.63)
    0.03 (0.03 to 0.04)
        Anti-6B [N=217;112]
    0.95 (0.76 to 1.2)
    0.03 (0.03 to 0.03)
        Anti-7F [N=217;110]
    3.33 (2.99 to 3.71)
    0.03 (0.03 to 0.04)
        Anti-9V [N=217;112]
    2.39 (2.06 to 2.76)
    0.04 (0.03 to 0.05)
        Anti-14 [N=217;112]
    3.8 (3.24 to 4.46)
    0.14 (0.11 to 0.17)
        Anti-18C [N=217;112]
    10.01 (8.49 to 11.8)
    0.03 (0.03 to 0.04)
        Anti-19F [N=217;111]
    7.65 (6.55 to 8.93)
    0.08 (0.07 to 0.1)
        Anti-23F [N=217;112]
    1.1 (0.91 to 1.33)
    0.03 (0.03 to 0.04)
    No statistical analyses for this end point

    Primary: Antibody concentrations against protein D (anti-PD antibodies)

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    End point title
    		 Antibody concentrations against protein D (anti-PD antibodies) [2]
    End point description
    Anti-PD antibody concentrations were tabulated, expressed in enzyme-linked immunorbent assay (ELISA) units per millilitre (EL.U/mL). Seropositivity cut-off for the assay was an anti-PD antibody concentrations >= 100 EL.U/mL.
    End point type
    Primary
    End point timeframe
    At Month 3, one month after the administration of the third dose of 10Pn-PD-DiT vaccine
    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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    217
    112
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-PD
    3791.8 (3448.4 to 4169.3)
    85.4 (71.8 to 101.5)
    No statistical analyses for this end point

    Secondary: Concentrations of antibodies against cross-reactive pneumococcal serotypes 6A and 19A (Anti-6A and -19A)

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    End point title
    		 Concentrations of antibodies against cross-reactive pneumococcal serotypes 6A and 19A (Anti-6A and -19A)
    End point description
    Seropositivity status was defined as anti-pneumococcal cross-reactive serotypes 6A/19A antibody concentrations (Anti-6A/19A) >= 0.05 microgram per milliliter (µg/mL).
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of 10Pn-PD-DiT vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    217
    108
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-6A
    0.09 (0.08 to 0.11)
    0.04 (0.04 to 0.05)
        Anti-19A
    0.15 (0.13 to 0.18)
    0.06 (0.05 to 0.07)
    No statistical analyses for this end point

    Secondary: Titers for opsonophagocytic activity (OPA) against vaccine pneumococcal serotypes

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    End point title
    		 Titers for opsonophagocytic activity (OPA) against vaccine pneumococcal serotypes
    End point description
    Pneumococcal serotypes assessed were vaccine pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. Seropositivity status was defined as an opsonophagocytic activity against vaccine pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (OPA-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) >= 8.
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of 10Pn-PD-DiT vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    105
    56
    Units: Titers
    geometric mean (confidence interval 95%)
        OPA-1 [N=105;56]
    83 (61.7 to 111.7)
    5 (3.8 to 6.4)
        OPA-4 [N=105;55]
    892.5 (759.4 to 1049)
    4.6 (3.9 to 5.5)
        OPA-5 [N=105;56]
    82.7 (65.4 to 104.4)
    4.5 (3.8 to 5.2)
        OPA-6B [N=103;54]
    538.6 (346 to 838.3)
    5.7 (4.1 to 7.9)
        OPA-7F [N=105;49]
    2733 (2188.3 to 3413.3)
    31.5 (15.5 to 64)
        OPA-9V [N=105;54]
    1023.7 (784.8 to 1335.2)
    8.4 (5.8 to 12.4)
        OPA-14 [N=104;53]
    1079.2 (776 to 1500.9)
    8.9 (5.7 to 14.1)
        OPA-18C [N=105;56]
    617.6 (495.3 to 770)
    4.4 (3.8 to 5.2)
        OPA-19F [N=105;56]
    358.3 (269.9 to 475.5)
    4.6 (3.8 to 5.7)
        OPA-23F [N=104;53]
    881.8 (615 to 1264.4)
    6.6 (4.2 to 10.3)
    No statistical analyses for this end point

    Secondary: Titers for opsonophagocytic activity (OPA) against cross-reactive pneumococcal serotypes

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    End point title
    		 Titers for opsonophagocytic activity (OPA) against cross-reactive pneumococcal serotypes
    End point description
    Pneumococcal serotypes assessed were cross-reactive pneumococcal serotypes 6A and 19A. Seropositivity status was defined as an opsonophagocytic activity against cross-reactive pneumococcal serotypes 6A and 19A (OPA-6A and 19A) >= 8.
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of 10Pn-PD-DiT vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    105
    56
    Units: Titres
    geometric mean (confidence interval 95%)
        OPA-6A [N=101;56]
    14.1 (9.4 to 21.2)
    6.1 (4.4 to 8.7)
        OPA-19A [N=105;56]
    11 (8.3 to 14.6)
    4.3 (4 to 4.6)
    No statistical analyses for this end point

    Secondary: Number of subjects seropositive for antibodies against vaccine pneumococcal serotypes

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    End point title
    		 Number of subjects seropositive for antibodies against vaccine pneumococcal serotypes
    End point description
    Pneumococcal serotypes assessed were vaccine pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. Seropositivity cut-off for the assay was an anti-pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F antibody (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) concentrations >= 0.05 microgram per milliliter (µg/mL).
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of 10Pn-PD-DiT vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    217
    108
    Units: Subjects
        Anti-1 [N=217;108]
    217
    14
        Anti-4 [N=217;112]
    217
    12
        Anti-5 [N=217;109]
    217
    18
        Anti-6B [N=217;112]
    196
    15
        Anti-7F [N=217;110]
    217
    19
        Anti-9V [N=217;112]
    213
    31
        Anti-14 [N=217;112]
    217
    91
        Anti-18C [N=217;112]
    216
    23
        Anti-19F [N=217;111]
    217
    73
        Anti-23F [N=217;112]
    207
    23
    No statistical analyses for this end point

    Secondary: Number of subjects seroprotected as regards antibodies against vaccine pneumococcal serotypes

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    End point title
    		 Number of subjects seroprotected as regards antibodies against vaccine pneumococcal serotypes
    End point description
    Pneumococcal serotypes assessed were vaccine pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. Seroprotection cut-off for the assay was an anti-pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F antibody (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) concentrations >= 0.2 microgram per milliliter (µg/mL).
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of 10Pn-PD-DiT vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    217
    112
    Units: Subjects
        Anti-1 [N=217;108]
    217
    2
        Anti-4 [N=217;112]
    217
    3
        Anti-5 [N=217;109]
    217
    4
        Anti-6B [N=217;112]
    178
    2
        Anti-7F [N=217;110]
    216
    2
        Anti-9V [N=217;112]
    211
    11
        Anti-14 [N=217;112]
    215
    40
        Anti-18C [N=217;112]
    216
    4
        Anti-19F [N=217;111]
    214
    25
        Anti-23F [N=217;112]
    190
    3
    No statistical analyses for this end point

    Secondary: Number of subjects seropositive as regards antibodies against cross-reactive pneumococcal serotypes 6A and 19A (Anti-6A and -19A).

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    End point title
    		 Number of subjects seropositive as regards antibodies against cross-reactive pneumococcal serotypes 6A and 19A (Anti-6A and -19A).
    End point description
    Serotypes assessed were cross-reactive pneumococcal serotypes 6A and 19A. Seropositivity status was defined as anti-pneumococcal cross-reactive serotypes 6A/19A antibody concentrations (Anti-6A/19A) >= 0.05 microgram per milliliter (µg/mL).
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of 10Pn-PD-DiT vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    217
    108
    Units: Subjects
        Anti-6A
    152
    36
        Anti-19A
    176
    49
    No statistical analyses for this end point

    Secondary: Number of subjects seroprotected as regards antibodies against cross-reactive pneumococcal serotypes 6A and 19A (Anti-6A and -19A).

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    End point title
    		 Number of subjects seroprotected as regards antibodies against cross-reactive pneumococcal serotypes 6A and 19A (Anti-6A and -19A).
    End point description
    Serotypes assessed were cross-reactive pneumococcal serotypes 6A and 19 A. Seroprotection cut-off for the assay was an anti-6A/19A antibody concentrations >= 0.2 microgram per milliliter (µg/mL).
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of 10Pn-PD-DiT vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    217
    108
    Units: Subjects
        Anti-6A
    56
    8
        Anti-19A
    95
    15
    No statistical analyses for this end point

    Secondary: Number of subjects seropositive as regards antibodies against protein D (Anti-PD antibodies)

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    End point title
    		 Number of subjects seropositive as regards antibodies against protein D (Anti-PD antibodies)
    End point description
    Seropositivity cut-off for the assay was an anti-PD antibody concentrations >= 100 EL.U/mL.
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of 10Pn-PD-DiT vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    217
    112
    Units: Subjects
        Anti-PD
    217
    34
    No statistical analyses for this end point

    Secondary: Number of subjects seropositive as regards opsonophagocytic activity against vaccine pneumococcal serotypes

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    End point title
    		 Number of subjects seropositive as regards opsonophagocytic activity against vaccine pneumococcal serotypes
    End point description
    Pneumococcal serotypes assessed were vaccine pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. Seropositivity status was defined as an opsonophagocytic activity against vaccine pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (OPA-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) >= 8.
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of 10Pn-PD-DiT vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    105
    56
    Units: Subjects
        OPA-1 [N=105;56]
    92
    3
        OPA-4 [N=105;55]
    105
    3
        OPA-5 [N=105;56]
    100
    2
        OPA-6B [N=103;54]
    88
    5
        OPA-7F [N=105;49]
    105
    21
        OPA-9V [N=105;54]
    103
    13
        OPA-14 [N=104;53]
    100
    13
        OPA-18C [N=105;56]
    103
    2
        OPA-19F [N=105;56]
    101
    2
        OPA-23F [N=104;53]
    97
    5
    No statistical analyses for this end point

    Secondary: Number of subjects seropositive as regards opsonophagocytic activity against cross-reactive pneumococcal serotypes

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    End point title
    		 Number of subjects seropositive as regards opsonophagocytic activity against cross-reactive pneumococcal serotypes
    End point description
    Pneumococcal serotypes assessed were cross-reactive pneumococcal serotypes 6A and 19A. Seropositivity status was defined as an opsonophagocytic activity against cross-reactive pneumococcal serotypes 6A and 19A (OPA-6A and 19A) >= 8.
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of 10Pn-PD-DiT vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    105
    56
    Units: Subjects
        OPA-6A [N=101;56]
    31
    6
        OPA-19A [N=105;56]
    39
    3
    No statistical analyses for this end point

    Secondary: Anti-Bordetella pertussis (anti-BPT) antibody concentrations

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    End point title
    		 Anti-Bordetella pertussis (anti-BPT) antibody concentrations
    End point description
    Anti-BPT antibody concentrations were measured, and tabulated in enzyme-linked immunosorbent assay (ELISA) unit per millilitre (EL.U/mL). Seropositivity cut-off for the assay was defined as an anti-BPT antibody concentrations >= 15 EL.U/mL
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of DTPw-HBV/Hib vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    110
    111
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-BPT
    111.9 (102 to 122.7)
    124.9 (111.7 to 139.7)
    No statistical analyses for this end point

    Secondary: Number of subjects seropositive as regards anti-Bordetella pertussis (anti-BPT) antibodies

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    End point title
    		 Number of subjects seropositive as regards anti-Bordetella pertussis (anti-BPT) antibodies
    End point description
    Seropositivity cut-off for the assay was defined as an anti-BPT antibody concentration >= 15 enzyme-linked immunosorbent assay (ELISA) unit per millilitre (EL.U/mL).
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of DTPw-HBV/Hib vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    110
    111
    Units: Subjects
        Anti-BPT
    110
    111
    No statistical analyses for this end point

    Secondary: Anti-diphtheria (Anti-D) and anti-tetanus toxoids (Anti-TT) antibody concentrations

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    End point title
    		 Anti-diphtheria (Anti-D) and anti-tetanus toxoids (Anti-TT) antibody concentrations
    End point description
    The seroprotection cut-off for the endpoint was an anti-diphtheria toxoid or anti-tetanus toxoid antibody concentrations >= 0.1 international unit per millliter (IU/mL).
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of DTPw-HBV/Hib vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    110
    112
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Anti-D
    4.103 (3.527 to 4.773)
    3.13 (2.731 to 3.588)
        Anti-T
    6.484 (5.511 to 7.628)
    4.588 (3.88 to 5.426)
    No statistical analyses for this end point

    Secondary: Number of subjects seroprotected as regards anti-diphtheria (Anti D) and anti-tetanus toxoids (Anti TT) antibodies

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    End point title
    		 Number of subjects seroprotected as regards anti-diphtheria (Anti D) and anti-tetanus toxoids (Anti TT) antibodies
    End point description
    A seroprotected subject as regards anti-D/-TT antibodies was defined as a subject with an Anti-D/-TT antibody concentration >= 0.1 international unit per millliter (IU/mL).
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of DTPw-HBV/Hib vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    110
    112
    Units: Subjects
        Anti-D
    110
    112
        Anti-T
    110
    112
    No statistical analyses for this end point

    Secondary: Anti-polyribosyl-ribitol-phosphate (Anti-PRP) antibody concentrations

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    End point title
    		 Anti-polyribosyl-ribitol-phosphate (Anti-PRP) antibody concentrations
    End point description
    Anti-PRP antibody concentrations were measured and tabulated in microgram per millilitre (µg/mL). Cut-off for the assay was >= 0.15 µg/mL.
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of DTPw-HBV/Hib vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    110
    112
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-PRP
    18.461 (14.256 to 23.907)
    10.137 (7.515 to 13.673)
    No statistical analyses for this end point

    Secondary: Number of subjects seroprotected as regards anti-polyribosyl-ribitol phosphate (anti-PRP) antibodies, for the >= 0.15 µg/mL cut-off

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    End point title
    		 Number of subjects seroprotected as regards anti-polyribosyl-ribitol phosphate (anti-PRP) antibodies, for the >= 0.15 µg/mL cut-off
    End point description
    Anti-PRP antibody concentrations were measured and tabulated in microgram per millilitre (µg/mL). The seroprotection cut-off applied for this endpoint was >= 0.15 µg/mL.
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of DTPw-HBV/Hib vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    110
    112
    Units: Subjects
        Anti-PRP
    110
    111
    No statistical analyses for this end point

    Secondary: Number of subjects seroprotected as regards anti-polyribosyl-ribitol phosphate (anti-PRP) antibodies, for the >= 1 µg/mL cut-off

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    End point title
    		 Number of subjects seroprotected as regards anti-polyribosyl-ribitol phosphate (anti-PRP) antibodies, for the >= 1 µg/mL cut-off
    End point description
    Anti-PRP antibody concentrations were measured and tabulated in microgram per millilitre (µg/mL). The seroprotection cut-off applied for this endpoint was >= 1 µg/mL.
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of DTPw-HBV/Hib vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    110
    112
    Units: Subjects
        Anti-PRP
    107
    102
    No statistical analyses for this end point

    Secondary: Anti-hepatitis B surface antigen (HBs) antibody concentrations

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    End point title
    		 Anti-hepatitis B surface antigen (HBs) antibody concentrations
    End point description
    The seroprotection cut-off for the endpoint was an an anti-HBs antibody concentration >= 10 milli-international units per millliter (mIU/mL). Please note that A decrease in the specificity of the anti-HBs Enzyme-Linked ImmunoSorbent Assay (ELISA) assay had been observed in some studies for low levels of antibody (10-100 mIU/mL). The results presented are updated results following partial or complete retesting/reanalysis.
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of DTPw-HBV/Hib vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    91
    96
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        Anti-HBs
    1835.1 (1384 to 2433.2)
    1485.5 (1198.7 to 1840.9)
    No statistical analyses for this end point

    Secondary: Number of subjects seroprotected as regards anti-Hepatitis B surface antigen (HBs) antibodies.

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    End point title
    		 Number of subjects seroprotected as regards anti-Hepatitis B surface antigen (HBs) antibodies.
    End point description
    The seroprotection cut-off values considered for this endpoint were an anti-HBs antibody concentration >= 10 and 100 milli-international units per millliter (mIU/mL). This follows from that a decrease in the specificity of the anti-HBs Enzyme-Linked ImmunoSorbent Assay (ELISA) assay had been observed in some studies for low levels of antibody (10-100 mIU/mL). The results presented are updated results following partial or complete retesting/reanalysis.
    End point type
    Secondary
    End point timeframe
    At Month 3, one month after the administration of the third dose of DTPw-HBV/Hib vaccine
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    91
    96
    Units: Subjects
        Anti-HBs >= 10 mIU/mL
    89
    96
        Anti-HBs >= 100 mIU/mL
    89
    94
    No statistical analyses for this end point

    Secondary: Number of subjects with any and any Grade 3 solicited local symptoms

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    End point title
    		 Number of subjects with any and any Grade 3 solicited local symptoms
    End point description
    Solicited local symptoms assessed include pain, redness and swelling. Grade 3 pain was defined as crying when limb was moved/spontaneously painful. Grade 3 swelling/redness was defined as swelling/redness larger than (>) 30 millimeters (mm). “Any” is defined as incidence of the specified symptom regardless of intensity.
    End point type
    Secondary
    End point timeframe
    Within the 4-day (Days 0 to 3) follow-up periods after each vaccination, across doses and across vaccines
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    239
    118
    Units: Subjects
        Any Pain
    234
    112
        Grade 3 Pain
    8
    3
        Any Redness
    57
    30
        Grade 3 Redness
    0
    0
        Any Swelling
    173
    83
        Grade 3 Swelling
    22
    11
    No statistical analyses for this end point

    Secondary: Number of subjects with any and any Grade 3 and related solicited general symptoms

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    End point title
    		 Number of subjects with any and any Grade 3 and related solicited general symptoms
    End point description
    Solicited general symptoms assessed include drowsiness, fever (defined as rectal temperature >= 38.0°C), irritability, and loss of appetite. “Any” is defined as incidence of the specified symptom regardless of intensity or relationship to study vaccination. Grade 3 drowsiness was defined as drowsiness which prevented normal everyday activities. Grade 3 fever was defined as fever (rectal temperature) above (>) 40.0 degree Celsius (°C). Grade 3 irritability was defined as crying that could not be comforted/preventing normal activity. Grade 3 loss of appetite was defined as the subject not eating at all.
    End point type
    Secondary
    End point timeframe
    Within the 4-day (Days 0 to 3) follow-up periods after each vaccination, across doses and across vaccines
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    239
    118
    Units: Subjects
        Any Drowsiness
    24
    12
        Grade 3 Drowsiness
    0
    0
        Any Fever (Rectally)
    207
    105
        Grade 3 Fever (Rectally)
    1
    0
        Any Irritability
    192
    88
        Grade 3 Irritability
    6
    2
        Any Loss of appetite
    37
    15
        Grade 3 Loss of appetite
    1
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with fever (temperature measured rectally > 39.0°C)

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    End point title
    		 Number of subjects with fever (temperature measured rectally > 39.0°C)
    End point description
    The level of fever (fever being as rectal temperature >= 38.0°C) assessed for this endpoint was > 39.0°C.
    End point type
    Secondary
    End point timeframe
    Within the 4-day (Days 0 to 3) follow-up periods after each vaccination, across doses and across vaccines
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    239
    118
    Units: Subjects
        Fever >39.0°C
    40
    13
    No statistical analyses for this end point

    Secondary: Number of subjects with unsolicited adverse events (AEs)

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    End point title
    		 Number of subjects with unsolicited adverse events (AEs)
    End point description
    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. “Any” was defined an incidence of an unsolicited AE regardless of intensity or relationship to study vaccination.
    End point type
    Secondary
    End point timeframe
    Within the 31-day (Days 0-30) follow-up periods post vaccination, across doses and across vaccines
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    239
    118
    Units: Subjects
        Any AEs
    176
    92
    No statistical analyses for this end point

    Secondary: Number of subjects with serious adverse events (SAEs)

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    End point title
    		 Number of subjects with serious adverse events (SAEs)
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout the entire study period, from Month 0 to Month 3
    End point values
    		 10Pn-PD-DiT/EPI Group EPI Group
    Number of subjects analysed
    239
    118
    Units: Subjects
        Any SAEs
    5
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited symptoms and unsolicited AEs: During the 4-day (Days 0-3) and 31-day (Days 0-30) post vaccination follow-up periods, respectively, across doses and across vaccines. SAEs: throughout the entire study period, from Month 0 to Month 3.
    Adverse event reporting additional description
    The occurrence of reported AEs (all/related) was not available and is encoded as equal to the number of subjects affected.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    EPI Group
    Reporting group description
    		 Subjects in this group received 3 doses of Expanded Program on Immunization (EPI) vaccines Zilbrix™ Hib (or DTPw-HBV/Hib) and Polio Sabin™ (or OPV) according to a 3-dose schedule at 6-10-14 weeks of age. The DTPw-HBV/Hib vaccine was administered by intramuscular injection, in the left thigh. The OPV vaccine was administered orally.

    Reporting group title
    10Pn-PD-DiT/EPI Group
    Reporting group description
    		 Subjects in this group received 3 doses of 10Pn-PD-DiT vaccine, GSK Biologicals’ 10-valent pneumococcal conjugate 1024850A vaccine (later marketed as Synflorix) according to a 3-dose schedule at 6-10-14 weeks of age co-administered with 3 doses of Expanded Program on Immunization (EPI) vaccines Zilbrix™ Hib (or DTPw-HBV/Hib) and Polio Sabin™ (or OPV) according to the same schedule. The 10Pn-PD-DiT and DTPw-HBV/Hib vaccines were administered by intramuscular injection, in the right and left thigh respectively. The OPV vaccine was administered orally.

    Serious adverse events
    		 EPI Group 10Pn-PD-DiT/EPI Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 118 (0.00%)
    5 / 239 (2.09%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Bronchopneumonia
         subjects affected / exposed
    0 / 118 (0.00%)
    4 / 239 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Malaria
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 EPI Group 10Pn-PD-DiT/EPI Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    112 / 118 (94.92%)
    234 / 239 (97.91%)
    General disorders and administration site conditions
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    112 / 118 (94.92%)
    234 / 239 (97.91%)
         occurrences all number
    112
    234
    Redness
    alternative assessment type: Systematic
         subjects affected / exposed
    30 / 118 (25.42%)
    57 / 239 (23.85%)
         occurrences all number
    30
    57
    Swelling
    alternative assessment type: Systematic
         subjects affected / exposed
    83 / 118 (70.34%)
    173 / 239 (72.38%)
         occurrences all number
    83
    173
    Drowsiness
    alternative assessment type: Systematic
         subjects affected / exposed
    12 / 118 (10.17%)
    24 / 239 (10.04%)
         occurrences all number
    12
    24
    Fever (rectal temperature >= 38.5°C)
    alternative assessment type: Systematic
         subjects affected / exposed
    105 / 118 (88.98%)
    207 / 239 (86.61%)
         occurrences all number
    105
    207
    Irritability
    alternative assessment type: Systematic
         subjects affected / exposed
    88 / 118 (74.58%)
    192 / 239 (80.33%)
         occurrences all number
    88
    192
    Loss of appetite
    alternative assessment type: Systematic
         subjects affected / exposed
    15 / 118 (12.71%)
    37 / 239 (15.48%)
         occurrences all number
    15
    37
    Injection site erosion
         subjects affected / exposed
    6 / 118 (5.08%)
    1 / 239 (0.42%)
         occurrences all number
    6
    1
    Injection site induration
         subjects affected / exposed
    20 / 118 (16.95%)
    22 / 239 (9.21%)
         occurrences all number
    20
    22
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    16 / 118 (13.56%)
    35 / 239 (14.64%)
         occurrences all number
    16
    35
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    22 / 118 (18.64%)
    43 / 239 (17.99%)
         occurrences all number
    22
    43
    Gastrointestinal disorder
         subjects affected / exposed
    15 / 118 (12.71%)
    25 / 239 (10.46%)
         occurrences all number
    15
    25
    Stomatitis
         subjects affected / exposed
    4 / 118 (3.39%)
    13 / 239 (5.44%)
         occurrences all number
    4
    13
    Respiratory, thoracic and mediastinal disorders
    Allergic bronchitis
         subjects affected / exposed
    46 / 118 (38.98%)
    83 / 239 (34.73%)
         occurrences all number
    46
    83
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 118 (5.08%)
    12 / 239 (5.02%)
         occurrences all number
    6
    12
    Ear infection
         subjects affected / exposed
    21 / 118 (17.80%)
    42 / 239 (17.57%)
         occurrences all number
    21
    42
    Gastroenteritis
         subjects affected / exposed
    32 / 118 (27.12%)
    61 / 239 (25.52%)
         occurrences all number
    32
    61
    Pharyngitis
         subjects affected / exposed
    5 / 118 (4.24%)
    14 / 239 (5.86%)
         occurrences all number
    5
    14
    Respiratory tract infection
         subjects affected / exposed
    11 / 118 (9.32%)
    17 / 239 (7.11%)
         occurrences all number
    11
    17
    Rhinitis
         subjects affected / exposed
    42 / 118 (35.59%)
    85 / 239 (35.56%)
         occurrences all number
    42
    85
    Skin infection
         subjects affected / exposed
    16 / 118 (13.56%)
    16 / 239 (6.69%)
         occurrences all number
    16
    16
    Urinary tract infection
         subjects affected / exposed
    8 / 118 (6.78%)
    3 / 239 (1.26%)
         occurrences all number
    8
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Feb 2008
    Amendment 1 was made in response to comments of the Ethics Committee of Mali and included the following changes: 1) Data and related publications on invasive pneumococcal disease in Mali were included; 2) Update on the presentation and administration of the OPV vaccine (Polio Sabin); 3) Update in the statistical analysis of safety; 4) Clarification on recording in the clinical report form (CRF) of administered vaccines other than the study vaccines; 5) Correction in the reference to the standard operating procedure (SOP) on destruction of used/unused vaccine vials/syringes/containers.
    17 Mar 2009
    Amendment 2 was made to include the following changes: 1) Planning of an interim analysis on all cleaned demographic, reactogenicity and immunogenicity data pertaining to Malian subjects enrolled by 31 December 2008; 2) Change in coordinating author and contributing authors.

    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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