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    Clinical Trial Results:
    A phase II, double-blind, randomized, placebo-controlled study to assess the safety, reactogenicity and immunogenicity of three doses of GlaxoSmithKline (GSK) Biologicals’ oral live attenuated human rotavirus (HRV) vaccine (RIX4414 at 10 Exp 6.5 CCID50) administered to human immunodeficiency virus (HIV) infected infants at 6, 10 and 14 weeks of age in South Africa.

    Summary
    EudraCT number
    		 2015-001484-39
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    13 Feb 2008

    Results information
    Results version number
    		 v2(current)
    This version publication date
    15 Nov 2020
    First version publication date
    19 Jul 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Results have been amended to account for consistency with other registries.

    Trial information

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    Trial identification
    Sponsor protocol code
    444563/022
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00263666
    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, 044 2089-904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, 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
    24 Jun 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Feb 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Feb 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and reactogenicity of 3 doses of GSK Biologicals’ HRV vaccine versus placebo in HIV infected infants.
    Protection of trial subjects
    The vaccinees were observed closely for at least 30 minutes, with appropriate medical treatment readily available in case of a rare anaphylactic reaction following the administration of vaccines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Mar 2005
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 100
    Worldwide total number of subjects
    100
    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)
    100
    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
    		 In case of discrepancy between the HIV results (DNA PCR positive, viral load negative), performed at the Screening Visit (one week prior to first vaccination) the infants were not enrolled in the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    The study was conducted in a double-blind manner. The parents/guardians of the subjects and the study personnel were unaware of the administered treatment (HRV vaccine or placebo).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rotarix Group
    Arm description
    		 Subjects received 3 doses of Rotarix vaccine co-administered with routine Tritanrix HepB Hib and Polio Sabin vaccines.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rotarix
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Oral vaccination

    Investigational medicinal product name
    Tritanrix-HB+Hib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Concomitant routine vaccination, IM administration

    Investigational medicinal product name
    PolioSabin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration, concomitant routine vaccination.

    Arm title
    		 Placebo Group
    Arm description
    		 Subjects received 3 doses of placebo co-administered with routine Tritanrix HepB Hib and Polio Sabin vaccines.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration.

    Investigational medicinal product name
    Tritanrix-HB+Hib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Concomitant routine vaccination, IM administration.

    Investigational medicinal product name
    PolioSabin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration, concomitant routine vaccination.

    Number of subjects in period 1
    		Rotarix Group Placebo Group
    Started
    50
    50
    Completed
    43
    39
    Not completed
    7
    11
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    6
    8
         Lost to follow-up
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rotarix Group
    Reporting group description
    		 Subjects received 3 doses of Rotarix vaccine co-administered with routine Tritanrix HepB Hib and Polio Sabin vaccines.

    Reporting group title
    Placebo Group
    Reporting group description
    		 Subjects received 3 doses of placebo co-administered with routine Tritanrix HepB Hib and Polio Sabin vaccines.

    Reporting group values
    		 Rotarix Group Placebo Group Total
    Number of subjects
    		 50 50 100
    Age categorical
    Units: Subjects
    Age continuous
    Units: weeks
        arithmetic mean (standard deviation)
    		 7.1 ± 1.1 6.9 ± 1.02 -
    Gender categorical
    Units: Subjects
        Female
    		 28 25 53
        Male
    		 22 25 47

    End points

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    End points reporting groups
    Reporting group title
    Rotarix Group
    Reporting group description
    		 Subjects received 3 doses of Rotarix vaccine co-administered with routine Tritanrix HepB Hib and Polio Sabin vaccines.

    Reporting group title
    Placebo Group
    Reporting group description
    		 Subjects received 3 doses of placebo co-administered with routine Tritanrix HepB Hib and Polio Sabin vaccines.

    Primary: Number of subjects reporting grade “2” or grade “3” fever, vomiting or diarrhea

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    End point title
    		 Number of subjects reporting grade “2” or grade “3” fever, vomiting or diarrhea [1]
    End point description
    Symptoms reported in the table include: Fever: temperature (axillary route) > 38.0 degree Celsius (°C); Diarrhea: ≥ 4 looser than normal stools/day; Vomiting: ≥ 2 episodes of vomiting/day.
    End point type
    Primary
    End point timeframe
    Within the 15-day solicited follow-up period after any dose
    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: This outcome was descriptive; hence no statistical analyses were required.
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    50
    50
    Units: Subjects
        Any symptom, Across Doses
    26
    28
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any unsolicited symptoms

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    End point title
    		 Number of subjects reporting any unsolicited symptoms
    End point description
    An unsolicited symptom was any spontaneously reported untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
    End point type
    Secondary
    End point timeframe
    Within 30 days after any dose
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    50
    50
    Units: Subjects
        Any symptom
    47
    48
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any serious adverse events

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    End point title
    		 Number of subjects reporting any serious adverse events
    End point description
    A serious adverse event (SAE) is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above.
    End point type
    Secondary
    End point timeframe
    Until 2 months after dose 3 (for subjects RV negative at Day 42 post-dose 3) or until end of RV shedding (for subjects who shed RV at Day 42 post-dose 3)
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    50
    50
    Units: Subjects
        Any SAE(s)
    17
    12
    No statistical analyses for this end point

    Secondary: Number of subjects reporting each type of solicited symptom

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    End point title
    		 Number of subjects reporting each type of solicited symptom
    End point description
    Solicited symptoms included Cough, Diarrhea (3 or more looser than normal stools/day), Fever (axillary temperature ≥ 37.5°C), Irritability, Loss of appetite, and Vomiting.
    End point type
    Secondary
    End point timeframe
    Within the 15-day solicited follow-up period after each dose
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    50
    50
    Units: Subjects
        Cough, after dose 1 (N=50,50)
    24
    25
        Diarrhoea, after dose 1 (N=50,50)
    8
    8
        Fever, after dose 1 (N=50,50)
    20
    19
        Irritability, after dose 1 (N=50,50)
    24
    24
        Loss of appetite, after dose 1 (N=50,50)
    18
    19
        Vomiting, after dose 1 (N=50,50)
    11
    10
        Cough, after dose 2 (N=46,48)
    18
    19
        Diarrhoea, after dose 2 (N=46,48)
    3
    7
        Fever, after dose 2 (N=46,48)
    15
    12
        Irritability, after dose 2 (N=46,48)
    20
    19
        Loss of appetite, after dose 2 (N=46,48)
    15
    15
        Vomiting, after dose 2 (N=46,48)
    9
    10
        Cough, after dose 3 (N=45,44)
    18
    17
        Diarrhoea, after dose 3 (N=45,44)
    7
    4
        Fever, after dose 3 (N=45,44)
    17
    13
        Irritability, after dose 3 (N=45,44)
    17
    18
        Loss of appetite, after dose 3 (N=45,44)
    10
    12
        Vomiting, after dose 3 (N=45,44)
    12
    6
    No statistical analyses for this end point

    Secondary: The number of subjects with no evidence of immunosuppression and moderate/severe suppresion, based on CD4+ absolute cell count and CD4+ percent

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    End point title
    		 The number of subjects with no evidence of immunosuppression and moderate/severe suppresion, based on CD4+ absolute cell count and CD4+ percent
    End point description
    Severe suppression: CD4+ cells/microliter (μl) < 750 and CD4+ percent < 15 percent (%); No evidence of suppression: CD4+ cells/μl ≥ 1500 and CD4+ percent ≥ 25%; Moderate suppression = all other CD4+ cell count and CD4+ % combinations.
    End point type
    Secondary
    End point timeframe
    At the screening visit and 2 months after dose 3 (Visit 4)
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    50
    50
    Units: Subjects
        Severe suppression at screening (n= 50, 50)
    1
    2
        Moderate suppression at screening (n= 50, 50)
    12
    15
        No suppression at screening (n= 50, 50)
    37
    33
        Severe suppression at Visit 4 (n= 43, 39)
    11
    7
        Moderate suppression at Visit 4 (n= 43, 39)
    15
    18
        No suppression at Visit 4 (n= 43, 39)
    13
    10
        Unknown at Visit 4 (n= 43, 39)
    4
    4
    No statistical analyses for this end point

    Secondary: Human immunodeficiency virus (HIV) Viral load

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    End point title
    		 Human immunodeficiency virus (HIV) Viral load
    End point description
    The HIV viral load was expressed as mean and standard deviation of the base-10 logarithm of HIV-1 ribonucleic acid (RNA) copies per milliliter (mL).
    End point type
    Secondary
    End point timeframe
    At the screening visit and 2 months after dose 3
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    50
    50
    Units: base-10 logarithm of copies/milliliter
    arithmetic mean (standard deviation)
        At screening (n= 50, 50)
    5.7 ± 0.52
    5.7 ± 0.51
        Two months after dose 3 (n= 43, 36)
    5.6 ± 0.77
    5.7 ± 0.51
    No statistical analyses for this end point

    Secondary: Number of subjects who seroconverted against rotavirus

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    End point title
    		 Number of subjects who seroconverted against rotavirus
    End point description
    A subject with anti-rotavirus Immunoglobulin (IgA) antibody concentration < 20 units/milliliter (U/mL) before vaccination and ≥ 20 U/mL after vaccination is considered as seroconverted.
    End point type
    Secondary
    End point timeframe
    Two months after dose 3
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    21
    22
    Units: Subjects
    12
    4
    No statistical analyses for this end point

    Secondary: Number of subjects with vaccine take

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    End point title
    		 Number of subjects with vaccine take
    End point description
    Vaccine take: appearance of serum IgA to rotavirus at a concentration of ≥ 20 U/ml or rotavirus shedding in any stool sample collected from the Screening Visit to 2 months after dose 3 for subjects initially negative for rotavirus.
    End point type
    Secondary
    End point timeframe
    Two months after dose 3
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    23
    22
    Units: Subjects
    15
    7
    No statistical analyses for this end point

    Secondary: Serum rotavirus immunoglobulin A (IgA) antibody concentrations

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    End point title
    		 Serum rotavirus immunoglobulin A (IgA) antibody concentrations [2]
    End point description
    Concentrations are given as geometric mean concentrations (GMC) for anti-rotavirus IgA antibodies.
    End point type
    Secondary
    End point timeframe
    Two months after dose 3
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In the Placebo Group, GMCs were all < 20 U/ml, hence values were not computed. Therefore, this outcome measure concerns subjects in Rotarix Group only.
    End point values
    		 Rotarix Group
    Number of subjects analysed
    21
    Units: U/ml
        geometric mean (confidence interval 95%)
    75.5 (29.1 to 195.7)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-polyribosyl ribitol phosphate (PRP) antibody concentrations more than or equal to the cut-off value

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    End point title
    		 Number of subjects with anti-polyribosyl ribitol phosphate (PRP) antibody concentrations more than or equal to the cut-off value
    End point description
    Cut-off values for anti-PRP antibody concentrations were ≥ 0.15 and ≥ 1.0 microgram/milliliter (µg/mL).
    End point type
    Secondary
    End point timeframe
    Two months after dose 3
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    25
    24
    Units: Subjects
        ≥ 0.15 µg/mL
    20
    23
        ≥ 1 µg/mL
    20
    22
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentration for anti-PRP antibodies

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    End point title
    		 Geometric Mean Concentration for anti-PRP antibodies
    End point description
    Anti-PRP antibody concentrations are presented as geometric mean concentrations, expressed in microgram/milliliter (μg/mL).
    End point type
    Secondary
    End point timeframe
    Two months after dose 3
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    25
    24
    Units: µg/mL
        geometric mean (confidence interval 95%)
    4.641 (1.764 to 12.215)
    4.865 (2.322 to 10.192)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-diphtheria and anti-tetanus toxoids antibody concentrations more than or equal to the cut-off value

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    End point title
    		 Number of subjects with anti-diphtheria and anti-tetanus toxoids antibody concentrations more than or equal to the cut-off value
    End point description
    The cut-off value was ≥ 0.1 International Units/milliliter (IU/mL).
    End point type
    Secondary
    End point timeframe
    Two months after dose 3
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    25
    25
    Units: Subjects
        Anti-diphtheria
    19
    19
        Anti-tetanus
    23
    24
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentration for anti-diphtheria and anti-tetanus toxoids antibodies

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    End point title
    		 Geometric Mean Concentration for anti-diphtheria and anti-tetanus toxoids antibodies
    End point description
    Anti-diphteria and anti-tetanus toxoids antibody concentrations are presented as geometric mean concentrations, expressed in international units/milliliter (IU/mL).
    End point type
    Secondary
    End point timeframe
    Two months after dose 3
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    25
    25
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Anti-tetanus
    1.457 (0.794 to 2.674)
    1.035 (0.647 to 1.656)
        Anti-diphtheria
    0.283 (0.167 to 0.481)
    0.219 (0.143 to 0.337)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-hepatitis B (HBs) antibody concentrations more than or equal to the cut-off value

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    End point title
    		 Number of subjects with anti-hepatitis B (HBs) antibody concentrations more than or equal to the cut-off value
    End point description
    The cut-off value was ≥ 10 milli international units/milliliter (mIU/mL).
    End point type
    Secondary
    End point timeframe
    Two months after dose 3
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    23
    20
    Units: Subjects
    15
    11
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentration for anti-HBs antibodies

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    End point title
    		 Geometric Mean Concentration for anti-HBs antibodies
    End point description
    Anti-HBs antibody concentrations are presented as geometric mean concentrations, expressed in milli international units/milliliter (mIU/mL).
    End point type
    Secondary
    End point timeframe
    Two months after dose 3
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    23
    20
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    25.6 (14.3 to 45.8)
    18.9 (9.9 to 36.1)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-Bordetella pertussis (BPT) antibody concentrations more than or equal to the cut-off value

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    End point title
    		 Number of subjects with anti-Bordetella pertussis (BPT) antibody concentrations more than or equal to the cut-off value
    End point description
    The cut-off value was ≥ 15 Enzyme Linked Immunosorbent Assay Unit/milliliter (EL.U/mL).
    End point type
    Secondary
    End point timeframe
    Two months after dose 3
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    25
    24
    Units: Subjects
    19
    14
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentration for anti-BPT antibodies

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    End point title
    		 Geometric Mean Concentration for anti-BPT antibodies
    End point description
    Anti-BPT antibody concentrations are presented as geometric mean concentrations, expressed in ELISA units/milliliter (EL.U/mL).
    End point type
    Secondary
    End point timeframe
    Two months after dose 3
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    25
    24
    Units: EL.U/mL
        geometric mean (confidence interval 95%)
    28.8 (19.3 to 42.8)
    18.1 (12.8 to 25.6)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-polio types 1, 2 and 3 antibody titers more than or equal to the cut-off value

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    End point title
    		 Number of subjects with anti-polio types 1, 2 and 3 antibody titers more than or equal to the cut-off value
    End point description
    The cut-off value was ≥ 1:8. The lowest dilution at which serum samples were tested was 1:8, from which a test was considered positive.
    End point type
    Secondary
    End point timeframe
    Two months after dose 3
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    25
    24
    Units: Subjects
        Anti-polio type 1 (n= 25, 24)
    19
    15
        Anti-polio type 2 (n= 25, 24)
    23
    21
        Anti-polio type 3 (n= 25, 23)
    18
    15
    No statistical analyses for this end point

    Secondary: Geometric Mean Titer for anti-polio types 1, 2 and 3 antibodies

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    End point title
    		 Geometric Mean Titer for anti-polio types 1, 2 and 3 antibodies
    End point description
    Anti-polio types 1, 2 and 3 antibody titers are presented as geometric mean titers.
    End point type
    Secondary
    End point timeframe
    Two months after dose 3
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    25
    24
    Units: Titers
    geometric mean (confidence interval 95%)
        Anti-polio 1 (n= 25, 24)
    90.5 (36.4 to 225.3)
    53 (19.4 to 144.5)
        Anti-polio 2 (n= 25, 24)
    142.6 (60.8 to 334.2)
    252.4 (91.2 to 698.7)
        Anti-polio 3 (n= 25, 23)
    44.7 (19.2 to 104.2)
    66 (22.6 to 192.2)
    No statistical analyses for this end point

    Secondary: Rotavirus antigen excretion in stool samples

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    End point title
    		 Rotavirus antigen excretion in stool samples
    End point description
    Number of subjects with rotavirus detected by Enzyme Linked Immunosorbent Assay (ELISA) in stool samples collected from Dose 1 until study end.
    End point type
    Secondary
    End point timeframe
    At day of each vaccination and at planned days following each vaccine dose until 2 months after dose 3 or until end of RV shedding
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    25
    25
    Units: Subjects
    11
    5
    No statistical analyses for this end point

    Secondary: Rotavirus in diarrheal stool samples

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    End point title
    		 Rotavirus in diarrheal stool samples
    End point description
    Number of subjects reporting at least one rotavirus (vaccine strain or wild type rotavirus) gastroenteritis episode.
    End point type
    Secondary
    End point timeframe
    From Dose 1 until 2 months after dose 3 or until end of RV shedding
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    50
    50
    Units: Subjects
        Subjects with at least 1 GE episode
    4
    4
    No statistical analyses for this end point

    Secondary: Enteric pathogens identification

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    End point title
    		 Enteric pathogens identification
    End point description
    Number of subjects reporting at least one episode of gastroenteritis (GE) classified by enteric pathogen tests results.
    End point type
    Secondary
    End point timeframe
    From Dose 1 until 2 months after dose 3 or until end of RV shedding
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    29
    34
    Units: Subjects
        Campylobacter, negative
    18
    24
        Campylobacter, positive
    0
    0
        Campylobacter, unknown
    11
    10
        E. histolytica, negative
    18
    24
        E. histolytica, positive
    0
    0
        E. histolytica, unknown
    11
    10
        Salmonella, negative
    17
    24
        Salmonella, positive
    1
    0
        Salmonella, unknown
    11
    10
        Sto Epec, negative
    3
    5
        Sto Epec, positive
    0
    0
        Sto Epec, unknown
    26
    29
        Sto G.Lamblia, negative
    18
    24
        Sto G.Lamblia, positive
    0
    0
        Sto G.Lamblia, unknown
    11
    10
        Sto Shigella, negative
    18
    24
        Sto Shigella, positive
    0
    0
        Sto Shigella, unknown
    11
    10
        Sto Yersinia, negative
    18
    24
        Sto Yersinia, positive
    0
    0
        Sto Yersinia, unknown
    11
    10
    No statistical analyses for this end point

    Secondary: Number of subjects with the RV in stool samples

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    End point title
    		 Number of subjects with the RV in stool samples
    End point description
    Number of subjects with presence of RV in stool samples (shedding) collected at pre-determined time points by RV type (Yes, No, Mixed type = G1V+G1WT+G2+G3+P4+P8V+P8WT and results not available [NA]).
    End point type
    Secondary
    End point timeframe
    From Dose 1 until post Dose 3
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    26
    7
    Units: Subjects
        Dose 1 (Day 7; Yes ) (N=9, 1)
    7
    0
        Dose 1 (Day 7; No) (N=9,1)
    0
    0
        Dose 1 (Day 7; NA) (N=9,1)
    2
    1
        Dose 1 (Day 14; Yes) (N=4,2)
    0
    0
        Dose 1 (Day 14; No) (N=4,2)
    0
    1
        Dose 1 (Day 14; Mixed) (N=4,2)
    0
    1
        Dose 1 (Day 14; NA) (N=4,2)
    4
    0
        Dose 1 (Day 21; Yes) (N=5,1)
    1
    0
        Dose 1 (Day 21; No) (N=5,1)
    0
    1
        Dose 1 (Day 21; NA) (N=5,1)
    4
    0
        Dose 2 (Day 7; Yes) (N=0,1)
    0
    0
        Dose 2 (Day 7; No) (N=0,1)
    0
    1
        Dose 2 (Day 7; NA) (N=0,1)
    0
    0
        Dose 2 (Day 14; Yes) (N=1,0)
    0
    0
        Dose 2 (Day 14; No) (N=1,0)
    0
    0
        Dose 2 (Day 14; NA) (N=1,0)
    1
    0
        Dose 2 (Day 21; Yes) (N=2,0)
    0
    0
        Dose 2 (Day 21; No) (N=2,0)
    0
    0
        Dose 2 (Day 21; NA) (N=2,0)
    2
    0
        Dose 3 (Day 7; Yes) (N=1,1)
    0
    0
        Dose 3 (Day 7; No) (N=1,1)
    0
    1
        Dose 3 (Day 7; NA) (N=1,1)
    1
    0
        Dose 3 (Day 14; Yes) (N=2,0)
    2
    0
        Dose 3 (Day 14; No) (N=2,0)
    0
    0
        Dose 3 (Day 14; NA) (N=2,0)
    0
    0
        Dose 3 (Day 42; Yes) (N=1,1)
    0
    0
        Dose 3 (Day 42; No) (N=1,1)
    0
    0
        Dose 3 (Day 42; NA) (N=1,1)
    1
    1
        Post Dose 3 (Day 0; Yes) (N=1,0)
    0
    0
        Post Dose 3 (Day 0; No) (N=1,0)
    0
    0
        Post Dose 3 (Day 0; NA) (N=1,0)
    1
    0
        Overall total (overall total; Yes) (N=26,7)
    10
    0
        Overall total (overall total; No) (N=26,7)
    0
    4
        Overall total (overall total;Mixed type) (N=26,7)
    0
    1
        Overall total (overall total; NA) (N=26,7)
    16
    2
    No statistical analyses for this end point

    Secondary: Rotavirus vaccine strain identification

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    End point title
    		 Rotavirus vaccine strain identification
    End point description
    Number of gastroenteritis (GE) episodes classified by rotavirus vaccine strain/serotype. Unknown: These samples were typed post hoc and found “G1P8” vaccine type for one subject in HRV group, “G3P8” and “G2P4” for subjects in placebo group.
    End point type
    Secondary
    End point timeframe
    From dose 1 until 2 months after dose 3 or until end of RV shedding
    End point values
    		 Rotarix Group Placebo Group
    Number of subjects analysed
    50
    50
    Units: Number of episodes
    number (not applicable)
        G1WT+P8WT
    2
    0
        G2+P4
    0
    1
        G3+P8
    0
    1
        GX+P6
    1
    0
        Unknown
    1
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited general symptoms during the 15-day (Days 0-14) post-vaccination period following each dose and across doses, unsolicited AEs within 31 days (Days 0-30) after any vaccination and SAEs throughout the study period.
    Adverse event reporting additional description
    The occurrence of reported AEs (all/related) was not available and encoded as equal to the number of subjects affected.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Rotarix Group
    Reporting group description
    		 Subjects received 3 doses of Rotarix vaccine co-administered with routine Tritanrix HepB Hib and Polio Sabin vaccines.

    Reporting group title
    Placebo Group
    Reporting group description
    		 Subjects received 3 doses of placebo co-administered with routine Tritanrix HepB Hib and Polio Sabin vaccines.

    Serious adverse events
    		 Rotarix Group Placebo Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 50 (34.00%)
    12 / 50 (24.00%)
         number of deaths (all causes)
    6
    9
         number of deaths resulting from adverse events
    6
    9
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden infant death syndrome
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus paralytic
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (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
    7 / 50 (14.00%)
    4 / 50 (8.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    1 / 2
    3 / 4
    Lobar pneumonia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumocystis jiroveci pneumonia
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Pneumonia
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Lymph node tuberculosis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Dysentery
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    6 / 50 (12.00%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    HIV infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Electrolyte imbalance
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Marasmus
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Rotarix Group Placebo Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 50 (96.00%)
    47 / 50 (94.00%)
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 50 (8.00%)
         occurrences all number
    1
    4
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    5 / 50 (10.00%)
    3 / 50 (6.00%)
         occurrences all number
    5
    3
    Splenomegaly
         subjects affected / exposed
    2 / 50 (4.00%)
    4 / 50 (8.00%)
         occurrences all number
    2
    4
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 50 (6.00%)
    6 / 50 (12.00%)
         occurrences all number
    3
    6
    Cough (solicited)
    alternative assessment type: Systematic
         subjects affected / exposed
    35 / 50 (70.00%)
    31 / 50 (62.00%)
         occurrences all number
    35
    31
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    16 / 50 (32.00%)
    16 / 50 (32.00%)
         occurrences all number
    16
    16
    Fever
    alternative assessment type: Systematic
         subjects affected / exposed
    30 / 50 (60.00%)
    28 / 50 (56.00%)
         occurrences all number
    30
    28
    Irritability
    alternative assessment type: Systematic
         subjects affected / exposed
    31 / 50 (62.00%)
    28 / 50 (56.00%)
         occurrences all number
    31
    28
    Loss of appetite
    alternative assessment type: Systematic
         subjects affected / exposed
    23 / 50 (46.00%)
    23 / 50 (46.00%)
         occurrences all number
    23
    23
    Vomiting (solicited)
    alternative assessment type: Systematic
         subjects affected / exposed
    19 / 50 (38.00%)
    15 / 50 (30.00%)
         occurrences all number
    19
    15
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 50 (6.00%)
         occurrences all number
    1
    3
    Vomiting
         subjects affected / exposed
    1 / 50 (2.00%)
    5 / 50 (10.00%)
         occurrences all number
    1
    5
    Abdominal pain
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 50 (6.00%)
         occurrences all number
    2
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 50 (2.00%)
    5 / 50 (10.00%)
         occurrences all number
    1
    5
    Nasal congestion
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 50 (8.00%)
         occurrences all number
    4
    4
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 50 (8.00%)
         occurrences all number
    4
    4
    Dermatitis diaper
         subjects affected / exposed
    5 / 50 (10.00%)
    4 / 50 (8.00%)
         occurrences all number
    5
    4
    Eczema
         subjects affected / exposed
    2 / 50 (4.00%)
    8 / 50 (16.00%)
         occurrences all number
    2
    8
    Rash
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 50 (4.00%)
         occurrences all number
    4
    2
    Rash papular
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 50 (36.00%)
    14 / 50 (28.00%)
         occurrences all number
    18
    14
    Pulmonary tuberculosis
         subjects affected / exposed
    2 / 50 (4.00%)
    4 / 50 (8.00%)
         occurrences all number
    2
    4
    Influenza
         subjects affected / exposed
    6 / 50 (12.00%)
    0 / 50 (0.00%)
         occurrences all number
    6
    0
    Pharyngitis
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 50 (6.00%)
         occurrences all number
    1
    3
    Bronchopneumonia
         subjects affected / exposed
    11 / 50 (22.00%)
    6 / 50 (12.00%)
         occurrences all number
    11
    6
    Gastroenteritis
         subjects affected / exposed
    9 / 50 (18.00%)
    9 / 50 (18.00%)
         occurrences all number
    9
    9
    Oral candidiasis
         subjects affected / exposed
    15 / 50 (30.00%)
    19 / 50 (38.00%)
         occurrences all number
    15
    19
    Otitis media
         subjects affected / exposed
    4 / 50 (8.00%)
    6 / 50 (12.00%)
         occurrences all number
    4
    6
    Sepsis
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 50 (0.00%)
         occurrences all number
    3
    0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 50 (0.00%)
         occurrences all number
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Nov 2004
    In response to comments from the Ethical committee of the WHO (SCRIHS), the following implementations were performed: • The study sites were described. Information on the pool from which subjects will be recruited as well as on the screening process was added. • The diagnostic plans for fatalities and their follow-up were described. • An Independent Data Monitoring Committee (IDMC) who is monitoring the safety aspects of GSK Biologicals’ HRV vaccine clinical development, will review each SAE/IS case and may recommend a clinical study hold in case of safety concern. • Since the study sites have different recommendations for the mother with regard to feeding the subjects, it was decided to record information on feeding practices. This will allow to explore any influence of feeding practice on vaccine take. • The safety data obtained with GSK Biologicals’ HRV vaccine since the finalization of the original protocol (dated 29 July 2003) were updated. • Other minor modifications (e.g. update of laboratory names and commercial kit versions for HIV testing; update to reflect the current processes to be followed for surgical specimens in case of IS) and administrative changes were made.
    19 Aug 2005
    • To update the safety data obtained with GSK Biologicals' HRV vaccine since the finalization of the original protocol and amendment 1 (dated 5 November 2004). • To update the Regulatory reporting requirements for serious adverse events according to latest version of GSK Biologicals' standard protocol. • Describe that GSK facilitate access to anti retroviral (ARV) treatment centers for subjects who develop clinical symptoms or have CD4 count below 20%. • To add the more recent description of immunologic and clinical categories of HIV disease: according to the WHO and Republic of South Africa (RSA) National guidelines. • To reflect other minor modifications (e.g. update of some laboratory tests and names of lab). • To reflect the IDMC's request to evaluate the presence of persistent or recurrent shedding of rotavirus at the final visit.

    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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