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    Clinical Trial Results:
    Combined treatment with pidotimod and bifidobacteria in pre-scholastic age children with recurrent respiratory infections: evaluation of clinical efficacy and parents' quality of life

    Summary
    EudraCT number
    		 2015-002733-22
    Trial protocol
    		 IT  
    Global end of trial date
    27 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jun 2018
    First version publication date
    28 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MB0515/1021/03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    VALEAS SPA
    Sponsor organisation address
    Via Vallisneri 10, MILANO, Italy, 20133
    Public contact
    Clinical Department, VALEAS SPA, 0039 0223690215, dir.medica@valeas.it
    Scientific contact
    Clinical Department, VALEAS SPA, 0039 0223690215, dir.medica@valeas.it
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate in pre-scholastic age children with recurrent respiratory infections the effects of the treatment with pidotimod and/or bifidobacteria on the prevention of respiratory infections.
    Protection of trial subjects
    At each visit, the investigator will evaluate the data reported in the diary to determine if and how many respiratory infections or what and how many adverse events will occur.
    Background therapy
    		 All drugs that subjects intake before enrollment are admitted, except immonu-modulating drugs, corticosteroids (except inhaled corticosteroids)
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Oct 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 2 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 98
    Worldwide total number of subjects
    98
    EEA total number of subjects
    98
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    98
    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
    		 All patients (n. 98) were recruited in Italy.

    Pre-assignment
    Screening details
    		 Children, aged 3-6 years, who go to the school and have recurrent respiratory infections in the last previous year were included. A total of 98 patients were randomized.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment A
    Arm description
    		 Pidotimod + Bifidobacteri
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pidotimod
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution in single-dose container
    Routes of administration
    Oral use
    Dosage and administration details
    1 single-dose container 400 mg, oral administration between meals, for 10 days at month for 4 months

    Investigational medicinal product name
    Bifidobacterium longum BB536, Bifidobacterium infantis M-63, Bifidobacterium breve M-16V
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules for oral suspension in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    1 sachet/die 5 billion Units in 3 g, oral administration between meals, 10 days at month for 4 months

    Arm title
    		 Treatment B
    Arm description
    		 Pidotimod + Placebo Pro
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pidotimod
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution in single-dose container
    Routes of administration
    Oral use
    Dosage and administration details
    1 single-dose container 400 mg, oral administration between meals, for 10 days at month for 4 months

    Investigational medicinal product name
    Placebo Probiotic
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    1 sachet/ die, oral administration between meals, for 10 days at month for 4 months

    Arm title
    		 Treatment C
    Arm description
    		 Placebo Imm + Bifidobacteri
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bifidobacterium longum BB536, Bifidobacterium infantis M-63, Bifidobacterium breve M-16V
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules for oral suspension in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    1 sachet/die 5 billion Units in 3 g, oral administration between meals, 10 days at month for 4 months

    Investigational medicinal product name
    Placebo Immunomodulant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution in single-dose container
    Routes of administration
    Oral use
    Dosage and administration details
    1 single-dose container, oral administration between meals, 10 days at month for 4 months

    Arm title
    		 Treatment D
    Arm description
    		 Placebo Pro + Placebo Imm
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo Probiotic
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    1 sachet/ die, oral administration between meals, for 10 days at month for 4 months

    Investigational medicinal product name
    Placebo Immunomodulant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution in single-dose container
    Routes of administration
    Oral use
    Dosage and administration details
    1 single-dose container, oral administration between meals, for 10 days at month for 4 months

    Number of subjects in period 1
    		Treatment A Treatment B Treatment C Treatment D
    Started
    25
    25
    23
    25
    Completed
    13
    13
    13
    16
    Not completed
    12
    12
    10
    9
         Lost to follow-up
    12
    12
    10
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment A
    Reporting group description
    		 Pidotimod + Bifidobacteri

    Reporting group title
    Treatment B
    Reporting group description
    		 Pidotimod + Placebo Pro

    Reporting group title
    Treatment C
    Reporting group description
    		 Placebo Imm + Bifidobacteri

    Reporting group title
    Treatment D
    Reporting group description
    		 Placebo Pro + Placebo Imm

    Reporting group values
    		 Treatment A Treatment B Treatment C Treatment D Total
    Number of subjects
    		 25 25 23 25 98
    Age categorical
    Units: Subjects
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 25 25 23 25 98
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 3.7 (3 to 6) 3.8 (3 to 6) 3.7 (3 to 6) 3.7 (3 to 6) -
    Gender categorical
    Units: Subjects
        Female
    		 11 9 10 12 42
        Male
    		 14 16 13 13 56
    Upper Tract Respiratory Infection
    Respiratory infections in the upper tract, which occurred during the previous year.
    Units: number
        arithmetic mean (full range (min-max))
    		 7.16 (1 to 13) 6.92 (1 to 13) 7.78 (1 to 18) 7.48 (5 to 12) -
    Lower Tract Respiratory Infection
    Respiratory infections in the lower tract, which occurred during the previous year.
    Units: number
        arithmetic mean (full range (min-max))
    		 0.96 (0 to 9) 1.24 (0 to 6) 0.74 (0 to 6) 1.12 (0 to 5) -
    Subject analysis sets

    Subject analysis set title
    Intention-to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who intake at least one dose of medication are included in the Intention-to-treat group

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who have the last visit after 6 months from randomization (4 months of treatment + 2 months of follow-up).

    Subject analysis sets values
    		 Intention-to-treat Per Protocol
    Number of subjects
    98
    55
    Age categorical
    Units: Subjects
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    98
    55
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    0
    0
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    3.8 (3 to 6)
    3.8 (3 to 6)
    Gender categorical
    Units: Subjects
        Female
    42
    21
        Male
    56
    34
    Upper Tract Respiratory Infection
    Respiratory infections in the upper tract, which occurred during the previous year.
    Units: number
        arithmetic mean (full range (min-max))
    7.33 (1 to 18)
    6.88 (1 to 13)
    Lower Tract Respiratory Infection
    Respiratory infections in the lower tract, which occurred during the previous year.
    Units: number
        arithmetic mean (full range (min-max))
    1.02 (0 to 9)
    1.00 (0 to 9)

    End points

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    End points reporting groups
    Reporting group title
    Treatment A
    Reporting group description
    		 Pidotimod + Bifidobacteri

    Reporting group title
    Treatment B
    Reporting group description
    		 Pidotimod + Placebo Pro

    Reporting group title
    Treatment C
    Reporting group description
    		 Placebo Imm + Bifidobacteri

    Reporting group title
    Treatment D
    Reporting group description
    		 Placebo Pro + Placebo Imm

    Subject analysis set title
    Intention-to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who intake at least one dose of medication are included in the Intention-to-treat group

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who have the last visit after 6 months from randomization (4 months of treatment + 2 months of follow-up).

    Primary: Number of Upper Tract Respiratory Infection

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    End point title
    		 Number of Upper Tract Respiratory Infection
    End point description
    This analysis has been performed in the Per Protocol population
    End point type
    Primary
    End point timeframe
    From randomization to the end of follow-up (6 months)
    End point values
    		 Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    13
    13
    13
    16
    Units: number
        arithmetic mean (confidence interval 95%)
    3.0 (1.9 to 4.1)
    4.1 (2.6 to 5.6)
    4.9 (3.8 to 6.0)
    3.6 (2.9 to 4.3)
    Statistical analysis title
    		 Treatment A vs Treatment D
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval
    Notes
    [1] - No statistical difference has been detected after ANOVA test
    Statistical analysis title
    		 Treatment A vs Treatment B
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval
    Notes
    [2] - No statistical difference has been detected after ANOVA test
    Statistical analysis title
    		 Treatment A vs Treatment C
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval
    Notes
    [3] - No statistical difference has been detected after ANOVA test

    Secondary: Duration of Upper Tract Respiratory Infection

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    End point title
    		 Duration of Upper Tract Respiratory Infection
    End point description
    This analysis has been performed on Per Protocol Population
    End point type
    Secondary
    End point timeframe
    From randomization to the end of follow-up (6 months)
    End point values
    		 Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    13
    13
    13
    16
    Units: day
        arithmetic mean (confidence interval 95%)
    21.2 (9.3 to 33.2)
    24.6 (10.8 to 38.4)
    36.6 (25.3 to 47.9)
    32.2 (18.7 to 45.6)
    No statistical analyses for this end point

    Secondary: Percent of days with Upper Tract Respiratory Infection

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    End point title
    		 Percent of days with Upper Tract Respiratory Infection
    End point description
    This analysis has been performed on Per Protocol Population
    End point type
    Secondary
    End point timeframe
    From randomization to the end of follow-up (6 months)
    End point values
    		 Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    13
    13
    13
    16
    Units: percent
        arithmetic mean (confidence interval 95%)
    11.9 (5.5 to 18.2)
    14.3 (6.1 to 22.4)
    20.2 (14.2 to 26.1)
    17.4 (10.7 to 24.1)
    Statistical analysis title
    		 Treatment A vs Treatment D
    Comparison groups
    Treatment A v Treatment D
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval
    Notes
    [4] - No significant difference has been detected in the ANOVA test
    Statistical analysis title
    		 Treatment A vs Treatment B
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval
    Notes
    [5] - No significant difference has been detected in the ANOVA test
    Statistical analysis title
    		 Treatment A vs Treatment C
    Comparison groups
    Treatment A v Treatment C
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval
    Notes
    [6] - No significant difference has been detected in the ANOVA test

    Secondary: Duration of each episode of Upper Tract Respiratory Infection

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    End point title
    		 Duration of each episode of Upper Tract Respiratory Infection
    End point description
    This analysis has been performed on Per Protocol Population
    End point type
    Secondary
    End point timeframe
    From randomization to the end of follow-up (6 months)
    End point values
    		 Treatment A Treatment B Treatment C Treatment D
    Number of subjects analysed
    13
    13
    13
    16
    Units: day
        arithmetic mean (confidence interval 95%)
    7.39 (2.8 to 12.0)
    4.74 (2.7 to 6.7)
    8.01 (5.4 to 10.6)
    8.04 (4.9 to 11.1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From randomization to the end of follow-up (6 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Intention-to-treat
    Reporting group description
    		 All patients who received at least a dose of study drug were included in the analysis.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: None non-serious adverse event has been reported during the study
    Serious adverse events
    		 Intention-to-treat
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 98 (1.02%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    		 Intention-to-treat
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 98 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jun 2016
    Substantial amendment to protocol was required to assess the metabolomic profile of urine before and after treatment and to prolong the enrolment period in order to reach the adequate population size. The sections of protocol amended were: rational, secondary endpoints, secondary variables, study procedure. The informed consent was consistently modified.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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