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    Clinical Trial Results:
    Randomized double-blind placebo-controlled prospective, parallel, multicentre clinical trial of bacterial vaccine (BACTEK ®) sublingual (oral mucosa) in patients with repeat bronchospasm for the immunomodulatory eficacy evaluation, security and clinical impact.

    Summary
    EudraCT number
    		 2012-002450-24
    Trial protocol
    		 ES  
    Global end of trial date
    24 May 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    30 Nov 2023
    First version publication date
    20 Nov 2021
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Typing errors corrections
    Summary report(s)
    		 Summary

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MV130-SLG-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01734811
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Inmunotek S.L.
    Sponsor organisation address
    C/ PUNTO MOBI, 5, Alcalá de Henares/ Madrid, Spain, 28805
    Public contact
    Miguel Casanovas; Medical Director, Inmunotek S.L., 34 916510010, mcasanovas@inmunotek.com
    Scientific contact
    Miguel Casanovas; Medical Director, Inmunotek S.L., 34 916510010, mcasanovas@inmunotek.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    24 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of a bacterial vaccine administered sublingually to prevent episodes of bronchospasm in patients with bronchospasm episodes induced by recurrent respiratory tract infections, compared with a placebo group
    Protection of trial subjects
    The subjects were not subjected to any technique that could cause them pain or be considered harmful to them
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    03 Sep 2012
    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
    Spain: 120
    Worldwide total number of subjects
    120
    EEA total number of subjects
    120
    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)
    59
    Children (2-11 years)
    61
    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
    		 The number of patients that were included in the study was 120 and those who finished were 113.

    Pre-assignment
    Screening details
    		 - Subjects whose parents /legal representative have given written informed consent. - Both gender - Subject up to 36 months of age. - Subjects with recurrent bronchospasms ; 3 or more exacerbations in the last 12 months

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active group
    Arm description
    		 The subjects will receive daily biological vaccines pray (2 puff of 100 µL) of for 6 months, followed by other 6 months of observation
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bactek
    Investigational medicinal product code
    MV130
    Other name
    Pharmaceutical forms
    Sublingual spray, solution
    Routes of administration
    Sublingual use
    Dosage and administration details
    2 daily spray (200 microlitres per day)

    Arm title
    		 Placebo
    Arm description
    		 The subjects will receive daily placebo spray (2 puff of 100 µL) of for 6 months, followed by other 6 months of observation
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Sublingual spray
    Routes of administration
    Sublingual use
    Dosage and administration details
    2 daily placebo spray (200 microlitres per day)

    Number of subjects in period 1
    		Active group Placebo
    Started
    62
    58
    Completed
    59
    54
    Not completed
    3
    4
         Adverse event, non-fatal
    -
    2
         Lost to follow-up
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 120 120
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 58 58
        Children (2-11 years)
    		 62 62
        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: months
        arithmetic mean (standard deviation)
    		 23.1 ± 7.7 -
    Gender categorical
    Units: Subjects
        Female
    		 50 50
        Male
    		 70 70

    End points

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    End points reporting groups
    Reporting group title
    Active group
    Reporting group description
    		 The subjects will receive daily biological vaccines pray (2 puff of 100 µL) of for 6 months, followed by other 6 months of observation

    Reporting group title
    Placebo
    Reporting group description
    		 The subjects will receive daily placebo spray (2 puff of 100 µL) of for 6 months, followed by other 6 months of observation

    Primary: Wheezing attacks (WA)

    		 Close Top of page
    End point title
    		 Wheezing attacks (WA)
    End point description
    Recurrent bronchospasm (wheezing attacks) during a period of 12 months after the initiation of the treatment. The number of bronchospasm (wheezing attacks) episodes between control and placebo groups were compared.
    End point type
    Primary
    End point timeframe
    One year per subject
    End point values
    		 Active group Placebo
    Number of subjects analysed
    62
    58
    Units: Percentage
        number (confidence interval 95%)
    2.8 (2.4 to 3.3)
    5.3 (4.5 to 6.2)
    Attachments
    		 End Point
    Statistical analysis title
    		 EPISODES OF WA BEFORE THE INITIATION OF TREATMENT
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.102 [2]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - Active group: The mean was 9.3 (8.2-10.4) and the median 8.0 (7.0-10.0). Placebo group: The mean was 10.3 (8.9-11.6) and the median 9.0 (7.0-11.3). Hodges-Lehman estimator was -1.0 (-2.0, 0.0)
    [2] - The differences between both groups of treatment were not significant.
    Statistical analysis title
    		 PREVIOUS MONTHLY WA
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.053 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - Active group: The mean was 0.8 (0.7-0.9) and the median 0.7 (0.6-0.8) Placebo group: The mean was 0.9 (0.8-1.1) and the median 0.8 (0.6-1.0). Hodges-Lehman estimator was -0.1 (-0.2, 0.0)
    [4] - The differences between both groups of treatment were not significant.
    Statistical analysis title
    		 EPISODES OF WA FROM MONTH 1 TO 12
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.001 [6]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - Active group: The mean was 2.8 (2.4-3.3) and the median 3.0 (2.0-4.0). Placebo group: The mean was 5.3 (4.5-6.2) and the median 5.0 (3.0-7.0) Hodges-Lehmann estimator was -2.0 (-3.0, -1.0)
    [6] - The active group had an improvement of 40% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 EPISODES OF WA DURING THE FIRST MONTH TREATMENT
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.054 [8]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [7] - Active group: The mean was 0.5 (0.3-0.7) and the median 0.0 (0.0-1.0). Placebo group: The mean was 0.8 (0.6-1.1) and the median 1.0 (0.0-1.0). The active group had an improvement of 100% over placebo. Hodges-Lehmann estimator was 0.0 (0.0, 0.0)
    [8] - The differences between both groups of treatment were not significant
    Statistical analysis title
    		 EPISODES OF WA DURING THE 2ND MONTH TREATMENT
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.063 [10]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [9] - Active group: The mean was 0.4 (0.2-0.5) and the median 0.0 (0.0-1.0) Placebo group: The mean was 0.6 (0.4-0.7) and the median 0.5 (0.0-1.0) Hodges-Lehmann estimator was 0.0 (0.0, 0.0)
    [10] - The differences between both groups of treatment were not significant.
    Statistical analysis title
    		 ACCUMMULATED WA DURING THE FIRST 2MONTHS TREATMENT
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.007 [12]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [11] - Active group: The mean was 0.9 (0.6-1.1) and the median 1.0 (0.0-1.0). Placebo group: The mean was 1.4 (1.1-1.7) and the median 1.0 (1.0-2.0). Hodges-Lehmann estimator was 0.0 (-1.0, 0.0)
    [12] - The differences between both groups of treatment were significant.
    Statistical analysis title
    		 EPISODES OF WA IN THE THIRD MONTH OF THE TREATMENT
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.022 [14]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [13] - Active group: The mean was 0.3 (0.2-0.5) and the median 0.0 (0.0-1.0) Placebo group: The mean was 0.6 (0.4-0.8) and the median 0.5 (0.0-1.0) Hodges-Lehmann estimator was 0.0 (0.0, 0.0)
    [14] - The active group had an improvement of 100% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 ACCUMULATED EPISODES WA DURING THE FIRST 3 MONTHS
    Statistical analysis description
    ACCUMULATED EPISODES OF WA DURING THE FIRST 3 MONTHS OF TREATMENT
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.002 [16]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [15] - Active group: The mean was 1.2 (0.9-1.4) and the median 1.0 (0.0-2.0). Placebo group: The mean was 2.0 (1.6-2.4) and the median 2.0 (1.0-3.0). Hodges-Lehmann estimator was -1.0 (-1.0, 0.0)
    [16] - The active group had an improvement of 50% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 EPISODES OF WA IN THE 4-5-6-MONTHS OF TREATMENT
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.018 [18]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [17] - Active group: The mean was 0.6 (0.4-0.8) and the median 0.0 (0.0-1.0). Placebo group: The mean was 1.1 (0.8-1.3) and the median 1.0 (0.0-2.0). Hodges-Lehmann estimator was 0.0 (-1.0, 0.0)
    [18] - The active group had an improvement of 100% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 ACCUMULATED EPISODES OF WA IN THE FIRST 6 MONTHS
    Statistical analysis description
    Accumulated episodes of WA in the first 6 months (period of treatment) of the clinical trial.v
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 < 0.001 [20]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [19] - Active group: The mean was 1.8 (1.5-2.1) and the median 2.0 (1.0-3.0). Placebo group: The mean was 3.1 (2.6-3.5) and the median 3.0 (2.0-4.0).
    [20] - The active group had an improvement of 33% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 EPISODES OF WA END OF 6 MONTHS -END OF THE TRIAL
    Statistical analysis description
    Episodes of WA from the end of the sixth month (end of the treatment) to the end of the trial.
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 < 0.001 [22]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [21] - Active group: The mean was 1.0 (0.7-1.4) and the median 1.0 (0.0-2.0). Placebo group: The mean was 2.3 (1.8-2.8) and the median 2.0 (1.0-3.0). Hodges-Lehmann estimator was -1.0 (-2.0, -1.0)
    [22] - The active group had an improvement of 50% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS W/WA AFTER THE INITIATION TO END TRIAL
    Statistical analysis description
    DAYS WITH WA AFTER THE INITIATION OF THE TREATMENT TO THE END OF THE TRIAL
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 < 0.001 [24]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [23] - Active group: The mean was 22.9 (18.0-27.8) and the median 19.0 (8.5-35.5). Placebo group: The mean was 46.1 (37.6-54.5) and the median 42.0 (21.5-59.8). Hodges-Lehmann estimator was -20.0 (-30.0, -11.0).
    [24] - The active group had an improvement of 55% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS WITH WA IN THE FIRST MONTH OF TREATMENT
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.122 [26]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [25] - Active group: The mean was 4.4 (2.7-6.1) and the median 0.0 (0.0-7.8) Placebo group: The mean was 6.9 (4.4-9.4) and the median 3.5 (0.0-11.0). Hodges-Lehmann estimator was 0.0 (-2.0, 0.0)
    [26] - The active group had an improvement of 100% over placebo. However, the differences between both groups of treatment were not significant.
    Statistical analysis title
    		 DAYS WITH WA IN THE SECOND MONTH OF TREATMENT
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.031 [28]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [27] - Active group: The mean was 3.0 (1.7-4.4) and the median 0.0 (0.0-4.0). Placebo group: The mean was 5.9 (3.8-7.9) and the median 2.0 (0.0-10.0). Hodges-Lehmann estimator was 0.0 (-2.0, 0.0)
    [28] - The active group had an improvement of 100% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS WITH WA IN THE THIRD MONTH OF TREATMENT
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.019 [30]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [29] - Active group: The mean was 2.3 (1.3-3.4) and the median 0.0 (0.0-3.0). Placebo group: The mean was 4.9 (3.3-6.6) and the median 1.5 (0.0-7.3). Hodges-Lehmann estimator was 0.0 (-3.0, 0.0)
    [30] - The active group had an improvement of 100% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS WITH WA IN THE 4-5-6 MONTHS OF TREATMENT
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.034 [32]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [31] - Active group: The mean was 4.5 (2.7-6.3) and the median 0.0 (0.0-6.8). Placebo group: The mean was 7.9 (5.4-10.5) and the median 5.5 (0.0-12.0). Hodges-Lehmann estimator was 0.0 (-5.0, 0.0)
    [32] - The active group had an improvement of 100% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS W/WA FROM END TREATMENT TO END TRIAL
    Statistical analysis description
    DAYS WITH WA FROM THE END OF TREATMENT TO THE END OF THE TRIAL
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 < 0.001 [34]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [33] - Active group: The mean was 8.6 (5.5-11.8) and the median 4.0 (0.0-11.8). Placebo group: The mean was 20.4 (15.2-25.5) and the median 19.0 (5.8-30.3). Hodges-Lehmann estimator was -10.0 (-15.0, -5.0)
    [34] - The active group had an improvement of 79% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 AVERAGE OF DAYS OF DURATION OF EACH WA
    Statistical analysis description
    AFTER THE INITIATION OF THE TREATMENT TO THE END OF THE TRIAL
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 = 0.005 [36]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [35] - Active group: The mean was 7.1 (5.8-8.5) and the median 6.0 (4.0-9.5). Placebo group: The mean was 8.9 (7.9-9.8) and the median 7.9 (6.2-11.0). Hodges-Lehmann estimator was -2.0 (-3.3, -0.6)
    [36] - The active group had an improvement of 24% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS FREE WA UNTIL 1ST EPISODE WA AFTER INITIATION
    Statistical analysis description
    AFTER THE INITIATION OF THE TREATMENT
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 < 0.001 [38]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [37] - Active group: The mean was 83.2 (56.1-110.2) and the median 41.0 (15.0-94.5). Placebo group: The mean was 22.5 (11.7-33.3) and the median 5.0 (2.0-29.8) Hodges-Lehmann estimator was 27.0 (14.0, 43.0) The Kaplan-Meier analysis showed that difference between both groups was significant
    [38] - Active group had an improvement of 88% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS FREE WA UNTIL 1ST EPISODE WA AFTER 1 MONTH
    Statistical analysis description
    AFTER 1 MONTH OF THE TREATMENT
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 = 0.004 [40]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [39] - Active group: The mean was 95.9 (68.1-123.6) and the median 56.5 (21.3-106.3) Placebo group: The mean was 48.3 (31.9-64.7) and the median 30.0 (11.8-54.3). Hodges-Lehmann estimator was 20.0 (6.0, 40.0) The Kaplan-Meier analysis showed that difference between both groups was significant
    [40] - Active group had an improvement of 47% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS FREE WA UNTIL 1ST EPISODE WA AFTER 2 MONTHS
    Statistical analysis description
    DAYS FREE OF WA UNTIL THE FIRST EPISODE OF WA AFTER 2 MONTHS OF THE TREATMENT
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 = 0.011 [42]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [41] - It was considered 305 days as the maximum possible value. Active group: The mean was 105.5 (77.2-133.7) and the median 60.5 (25.0- 120.0). Placebo group: The mean was 65.8 (42.3-89.3) and the median 27.0 (11.8-83.3). Hodges-Lehmann estimator was 19.0 (3.0, 42.0) The Kaplan-Meier analysis showed that the difference between both groups was significant
    [42] - Active group had an improvement of 55% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS FREE WA UNTIL 1ST EPISODE WA AFTER 3 MONTHS
    Statistical analysis description
    DAYS FREE OF WA UNTIL THE FIRST EPISODE OF WA AFTER 3 MONTHS OF THE TREATMENT
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 = 0.087 [44]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [43] - It was considered 275 days as the maximum possible value. Active group: The mean was 108.1 (80.2-136.1) and the median 57.0 (18.0-275.0). Placebo group: The mean was 74.3 (50.8-97.8) and the median 30.5 (13.5-112.0). Hodges-Lehmann estimator was 14.0 (0.0, 40.0) The Kaplan-Meier analysis showed that difference between both groups was not significant.
    [44] - Active group had an improvement of 46% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS FREE WA UNTIL 1ST EPISODE WA AFTER 6 MONTHS
    Statistical analysis description
    DAYS FREE OF WA UNTIL THE FIRST EPISODE OF WA AFTER THE END (6 MONTHS) OF THE TREATMENT
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 < 0.001 [46]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [45] - It was considered 180 (half year) as the maximum possible value. Active group: The mean was 120.8 (103.3-138.2) and the median 180.0 (48.5-180.0). Placebo group: The mean was 76.9 (59.3-94.6) and the median 44.5 (20.0-121.5). Hodges-Lehmann estimator was 41.0 (6.0, 66.0) The Kaplan-Meier analysis showed that the difference between both groups was significant
    [46] - Active group had an improvement of 75% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL DAYS FREE OF WA
    Statistical analysis description
    TOTAL DAYS FREE OF WA
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [47]
    P-value
    		 < 0.001 [48]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [47] - Active group: The mean was 337.1 (332.2-342.0) and the median 341.0 (324.5-351.5). Placebo group: The mean was 313.9 (305.5-322.4) and the median 318.0 (300.3-338.5). Hodges-Lehmann estimator was 20.0 (11.0, 30.0)
    [48] - Active group had an improvement of 7% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS WITHOUT WA IN THE FIRST MONTH
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [49]
    P-value
    		 = 0.122 [50]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [49] - Active group: The mean was 25.6 (24.0-27.3) and the median 30.0 (30.0-22.3). Placebo group: The mean was 23.2 (20.7-25.6) and the median 26.5 (19.0-30.0). Hodges-Lehmann estimator was 0.0 (0.0, 3.0)
    [50] - Active group had an improvement of 12% over placebo. The differences between both groups of treatment were not significant.
    Statistical analysis title
    		 DAYS WITHOUT WA IN THE FIRST TWO MONTHS
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [51]
    P-value
    		 = 0.013 [52]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [51] - Active group: The mean was 52.6 (50.5-54.7) and the median 56.0 (47.3-60.0). Placebo group: The mean was 47.2 (43.8-50.6) and the median 50.0 (40.0-58.0). Hodges-Lehmann estimator was 4.0 (0.0, 8.0)
    [52] - Active group had an improvement of 11% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS WITHOUT WA IN THE FIRST THREE MONTH
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [53]
    P-value
    		 = 0.002 [54]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [53] - Active group: The mean was 80.3 (77.8-82.8) and the median 82.5 (74.0-90.0). Placebo group: The mean was 72.3 (68.2-76.3) and the median 74.5 (65.0-82.3) Hodges-Lehmann estimator was 7.0 (2.0, 10.0)
    [54] - Active group had an improvement of 10% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS WITHOUT WA IN THE FIRST SIX MONTH
    Statistical analysis description
    DAYS WITHOUT WA IN THE FIRST SIX MONTH
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [55]
    P-value
    		 < 0.001 [56]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [55] - Active group: The mean was 165.7 (162.6-168.9) and the median 168.5 (157.8-176.0). Placebo group: The mean was 154.3 (149.2-159.4) and the median 159.0 (142.8-168.3). Hodges-Lehmann estimator was 10.0 (5.0, 14.0)
    [56] - Active group had an improvement of 6% over placebo. The differences between both groups of treatment were significant.

    Secondary: Symptom (SS) and medication (MS)

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    End point title
    		 Symptom (SS) and medication (MS)
    End point description
    Symptom (SS) and medication (MS) scores and the combination of both (SMS) during the WA. Review of medication consumed from the beginning to the end of the wheezing attacks per subject
    End point type
    Secondary
    End point timeframe
    One year
    End point values
    		 Active group Placebo
    Number of subjects analysed
    62
    58
    Units: percentage
        number (confidence interval 95%)
    1088.3 (922.1 to 1254.4)
    1760.9 (1505.9 to 2016.0)
    Statistical analysis title
    		 DAYS WITH NASAL MUCUS SECRETION
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [57]
    P-value
    		 = 0.005 [58]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [57] - Active group: The mean was 76.7 (61.7-91.6) and the median 71.0 (32.0-101.3). Placebo group: The mean was 108.0 (90.6-125.4) and the median 100.5 (61.8-146.8). Hodges-Lehman estimator was -33.0 (-55.0, -10.0).
    [58] - The active group had an improvement of 29% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS WITH FEVER
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [59]
    P-value
    		 = 0.068 [60]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [59] - Active group: The mean was 10.2 (8.4-12.0) and the median 9.5 (5.0-14.0). Placebo group: The mean was 15.8 (12.2-19.5) and the median 11.5 (7.0-20.5). Hodges-Lehman estimator was -3.0 (-7.0, -0.0).
    [60] - The active group had an improvement of 17% over placebo. The differences between both groups of treatment were not significant.
    Statistical analysis title
    		 DAYS WITH BRONCHIAL MUCUS SECRETION
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [61]
    P-value
    		 = 0.008 [62]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [61] - Active group: The mean was 30.0 (22.4-37.7) and the median 21.0 (8.0-42.5). Placebo group: The mean was 53.2 (39.1-67.3) and the median 41.0 (14.8-73.0). Hodges-Lehman estimator was -14.0 (-28.0, -4.0)
    [62] - The active group had an improvement of 49% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS WITH COUGH
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [63]
    P-value
    		 = 0.013 [64]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [63] - Active group: The mean was 69.5 (54.2-84.8) and the median 54.5 (26.0-87.0). Placebo group: The mean was 85.7 (72.3-99.1) and the median 78.5 (53.0-113.0). Hodges-Lehman estimator was -22.0 (-37.0, -4.0)
    [64] - The active group had an improvement of 31% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS WITH DYSPNOEA
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [65]
    P-value
    		 = 0.003 [66]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [65] - Active group: The mean was 14.7 (9.9-19.5) and the median 8.5 (1.3-18.0). Placebo group: The mean was 32.7 (20.7-44.8) and the median 19.5 (6.8-43.3). Hodges-Lehman estimator was -8.0 (-16.0, -2.0)
    [66] - The active group had an improvement of 56% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS WITH WHEEZING
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [67]
    P-value
    		 < 0.001 [68]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [67] - The mean was 11.5 (7.2-15.8) and the median 5.0 (0.0-14.0) The mean was 32.2 (20.4-44.1) and the median 19.0 (7.0-44.0). Hodges-Lehman estimator was -11.0 (-18.0, -6.0)
    [68] - The active group had an improvement of 74% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 DAYS WITH DISCOMFORT
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [69]
    P-value
    		 = 0.01 [70]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [69] - Active group: The mean was 20.7 (13.8-27.7) and the median 11.0 (3.3-32.3). Placebo group: The mean was 33.6 (24.4-42.9) and the median 20.0 (13.8-42.3). Hodges-Lehman estimator was -10.0 (-16.0, -2.0).
    [70] - The active group had an improvement of 45% over placebo. The differences between both groups of treatment were significant.

    Secondary: Symptom (SS) and medication scores (MS) and the combination of both (SMS

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    End point title
    		 Symptom (SS) and medication scores (MS) and the combination of both (SMS
    End point description
    Symptom (SS) and medication scores (MS) and the combination of both (SMS) during all the study
    End point type
    Secondary
    End point timeframe
    One year
    End point values
    		 Active group Placebo
    Number of subjects analysed
    62
    58
    Units: Percentage
        number (confidence interval 95%)
    330.8 (252.8 to 408.7)
    796.4 (611.6 to 981.2)
    Statistical analysis title
    		 TOTAL SYMPTOM SCORE DURING THE WA
    Statistical analysis description
    It includes the score of all the symptoms during the WA (fever, nasal mucus, bronchial mucus, cough, dyspnoea, wheezing and discomfort). The maximum possible daily value was 19.
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [71]
    P-value
    		 < 0.001 [72]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [71] - Active group: The mean was 106.1 (78.9-133.2) and the median 80.0 (19.5-154.5). Placebo group: The mean was 230.8 (164.7-296.8) and the median 168.0 (91.8-253.3). Hodges-Lehmann estimator was -75.0 (-113.0, -40.0)
    [72] - The active group had an improvement of 52% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL NORMALIZED MEDICATION SCORE DURING THE WA
    Statistical analysis description
    The maximum value of symptom scores during the WA was 19 and the corresponding medication scores was 24. Therefore, for the combination of both scores, medication score was adjusted to have the same weight as symptom by a factor of 0.79 (the ratio between 19 and 24).
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [73]
    P-value
    		 < 0.001 [74]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [73] - Active group: The mean was 224.7 (167.1-282.3) and the median 164.0 (43.5-311.5). Placebo group: The mean was 565.6 (426.3-704.9) and the median 456.0 (205.5-765.8). Hodges-Lehmann estimator was -240.5 (-386.0, -143.0).
    [74] - The active group had an improvement of 64% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL COMBINATION OF SS AND MS DURING THE WA
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [75]
    P-value
    		 < 0.001 [76]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [75] - Active group: The mean was 330.8 (252.8-408.7) and the median 277.5 (60.8-514.5). Placebo group: The mean was 796.4 (611.6-981.2) and the median 600.0 (282.5-1095.3). Hodges-Lehmann estimator was -329.5 (-511.0, -188.0)
    [76] - The active group had an improvement of 54% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 OVERALL SYMPTOM SCORE
    Statistical analysis description
    As descriptive statistics, the results were expressed as the mean (with the 95% confidence interval) and the median (with first and third quartile: IQ range).
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [77]
    P-value
    		 = 0.001 [78]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [77] - Active group: The mean was 319.9 (258.2-381.7) and the median 276.5 (151.0-426.0). Placebo group: The mean was 522.3 (410.1-634.5) and the median 421.0 (303.0-673.0). Hodges-Lehman estimator was -147.0 (-248.0, -63.0)
    [78] - The active group had an improvement of 34% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL SYMPTOM SCORE IN THE FIRST THREE MONTHS
    Statistical analysis description
    As descriptive statistics, the results were expressed as the mean (with the 95% confidence interval) and the median (with first and third quartile: IQ range).
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [79]
    P-value
    		 = 0.031 [80]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [79] - Active group: The mean was 150.0 (120.1-181.5) and the median 121.5 (57.8-215.8). Placebo group: The mean was 217.3 (165.3-269.3) and the median 165.5 (100.0-273.3). Hodges-Lehman estimator was -44.0 (-87.0, -4.0)
    [80] - The active group had an improvement of 27% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL SYMPTOM SCORE IN THE FIRST SIX MONTHS
    Statistical analysis description
    As descriptive statistics, the results were expressed as the mean (with the 95% confidence interval) and the median (with first and third quartile: IQ range).
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [81]
    P-value
    		 = 0.017 [82]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [81] - Active group: The mean was 237.8 (190.8-284.9) and the median 215.0 (112.0-320.5). Placebo group: The mean was 357.3 (271.2-443.4) and the median 290.5 (163.5-452.8) Hodges-Lehman estimator was -75.5 (-146.0, -15.0)
    [82] - The active group had an improvement of 26% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL SYMPTOM SCORE FROM SIX TO TWELVE MONTHS
    Statistical analysis description
    As descriptive statistics, the results were expressed as the mean (with the 95% confidence interval) and the median (with first and third quartile: IQ range).
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [83]
    P-value
    		 = 0.001 [84]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [83] - Active group: The mean was 75.6 (52.2-98.9) and the median 42.0 (17.0-102.5). Placebo group: The mean was 154.7 (111.6-197.7) and the median 110.0 (53.8-187.5). Hodges-Lehman estimator was -50.0 (-81.0, -21.0).
    [84] - The active group had an improvement of 62% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL SCORE OF RESPIRATORY SYMPTOMS
    Statistical analysis description
    Respiratory symptoms are cough, dyspnoea and wheezing
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [85]
    P-value
    		 = 0.002 [86]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [85] - Active group: The mean was 133.9 (107.0-160.8) and the median 115.0 (53.8-165.5). Placebo group: The mean was 222.6 (166.8-278.3) and the median 157.0 (110.0-295.3). Hodges-Lehman estimator was -53.0 (-97.0, -21.0)
    [86] - The active group had an improvement of 27% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL SCORE OF OTHER SYMPTOMS
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [87]
    P-value
    		 = 0.001 [88]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [87] - Active group: The mean was 186.0 (148.0-224.0) and the median 152.0 (73.3-262.0). Placebo group: The mean was 299.7 (239.6-359.8) and the median 253.5 (175.3-353.8). Hodges-Lehman estimator was -84.0 (-151.0, -38.0).
    [88] - The active group had an improvement of 40% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL SCORE OF NASAL MUCUS SECRETION
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [89]
    P-value
    		 = 0.004 [90]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [89] - Active group: The mean was 103.1 (81.4-124.9) and the median 82.0 (42.0-147.8). Placebo group: The mean was 152.4 (123.7-181.2) and the median 123.0 (83.8-199.5). Hodges-Lehman estimator was -44.0 (-75.0, -12.0).
    [90] - The active group had an improvement of 33% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL SCORE OF BRONCHIAL MUCUS SECRETION
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [91]
    P-value
    		 = 0.005 [92]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [91] - Active group: The mean was 42.7 (30.9-54.5) and the median 29.0 (11.0-59.0). Placebo group: The mean was 80.3 (57.5-103.1) and the median 58.5 (24.0-102.5) Hodges-Lehman estimator was -21.0 (-41.0, -6.0).
    [92] - The active group had an improvement of 50% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL SCORE OF COUGH
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [93]
    P-value
    		 = 0.02 [94]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [93] - Active group: The mean was 97.7 (76.2-119.2) and the median 83.0 (35.5-119.5). Placebo group: The mean was 126.4 (103.0-149.8) and the median 104.5 (72.0-153.5). Hodges-Lehman estimator was -30.0 (-54.0, -5.0)
    [94] - The active group had an improvement of 21% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL SCORE OF DYSPNOEA
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [95]
    P-value
    		 = 0.004 [96]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [95] - Active group: The mean was 20.7 (14.1-27.3) and the median 11.0 (2.0-26.5). Placebo group: The mean was 49.4 (29.6-69.3) and the median 25.5 (10.0-62.8). Hodges-Lehman estimator was -11.0 (-21.0, -3.0)
    [96] - The active group had an improvement of 57% over placebo. The differences between both groups of treatment were significant
    Statistical analysis title
    		 TOTAL SCORE OF WHEEZING
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [97]
    P-value
    		 < 0.001 [98]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [97] - Active group: The mean was 15.5 (9.9-21.2) and the median 6.5 (0.0-20.8). Placebo group: The mean was 46.7 (28.2-65.2) and the median 25.5 (8.5-61.5). Hodges-Lehman estimator was -15.0 (-24.0, -6.0)
    [98] - The active group had an improvement of 75% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL SCORE OF DISCOMFORT
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [99]
    P-value
    		 = 0.01 [100]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [99] - Active group: The mean was 30.0 (20.3-39.7) and the median 14.5 (4.0-47.5). Placebo group: The mean was 51.1 (36.2-66.0) and the median 31.0 (18.8-59.5). Hodges-Lehman estimator was -14.0 (-23.0, -3.0)
    [100] - The active group had an improvement of 53% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL MEDICATION SCORE
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [101]
    P-value
    		 < 0.001 [102]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [101] - Active group: The mean was 768.4 (636.1-900.6) and the median 681.5 (318.3-1033.5). Placebo group: The mean was 1238.6 (1035.4-1441.8) and the median 1043.5 (669.5-1696.0). Hodges-Lehman estimator was -403.5 (-647.0, -191.0).
    [102] - The active group had an improvement of 35% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL MEDICATION SCORE IN THE FIRST THREE MONTHS
    Statistical analysis description
    As descriptive statistics, the results were expressed as the mean (with the 95% confidence interval) and the median (with first and third quartile: IQ range)
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [103]
    P-value
    		 = 0.003 [104]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [103] - Active group: The mean was 319.9 (268.4-371.3) and the median 311.0 (133.8-487.8). Placebo group: The mean was 486.1 (404.6-567.6) and the median 406.5 (260.3-715.5). Hodges-Lehman estimator was -142.5 (-236.0, -49.0)
    [104] - The active group had an improvement of 23% over placebo. The differences between both groups of treatment were significant
    Statistical analysis title
    		 TOTAL MEDICATION SCORE IN THE FIRST SIX MONTHS
    Statistical analysis description
    As descriptive statistics, the results were expressed as the mean (with the 95% confidence interval) and the median (with first and third quartile: IQ range).
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [105]
    P-value
    		 = 0.002 [106]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [105] - Active group: The mean was 562.4 (468.7-656.0) and the median 509.5 (265.3-773.5). Placebo group: The mean was 846.7 (713.6-979.9) and the median 776.0 (470.5-1191.5). Hodges-Lehman estimator was -249.0 (-217.0, -100.0)
    [106] - The active group had an improvement of 34% over placebo. The differences between both groups of treatment were significant
    Statistical analysis title
    		 TOTAL MEDICATION SCORE FROM SIX TO TWELVE MONTHS
    Statistical analysis description
    As descriptive statistics, the results were expressed as the mean (with the 95% confidence interval) and the median (with first and third quartile: IQ range).
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [107]
    P-value
    		 < 0.001 [108]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [107] - Active group: The mean was 220.6 (165.1-276.0) and the median 187.0 (53.0-312.5). Placebo group: The mean was 406.4 (305.9-507.0) and the median 302.5 (103.8-488.3). Hodges-Lehman estimator was -136.0 (-204.0, -64.0)
    [108] - The active group had an improvement of 38% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL SCORE OF ANTIBIOTICS
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [109]
    P-value
    		 = 0.013 [110]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [109] - Active group: The mean was 32.8 (23.0-42.7) and the median 22.5 (6.0-44.5). Placebo group: The mean was 54.8 (39.8-69.8) and the median 41.5 (18.8-77.3). Hodges-Lehman estimator was -16.0 (-28.0, -2.0).
    [110] - The active group had an improvement of 46% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL SCORE OF ANTIPYRETIC/ANTI-INFLAMMATORY
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [111]
    P-value
    		 = 0.064 [112]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [111] - Active group: The mean was 40.1 (30.3-50.0) and the median 31.0 (18.0-50.5). Placebo group: The mean was 72.9 (51.1-94.8) and the median 38.5 (19.5-98.3). Hodges-Lehman estimator was -12.0 (-29.0, 0.0)
    [112] - The active group had an improvement of 19% over placebo. The differences between both groups of treatment were not significant.
    Statistical analysis title
    		 TOTAL SCORE BETA2-AGONISTS,INHL CORTICOS,MONTELUKA
    Statistical analysis description
    TOTAL SCORE OF BETA2-AGONISTS, INHALED CORTICOSTEROIDS AND MONTELUKAST
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [113]
    P-value
    		 < 0.001 [114]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [113] - Active group: The mean was 521.8 (422.6-621.0) and the median 435.5 (221.5-696.3). Placebo group: The mean was 919.2 (745.9-1092.5) and the median 818.5 (486.8-1275.0). Hodges-Lehman estimator was -323.0 (-487.0, -168.0).
    [114] - The active group had an improvement of 47% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL SCORE OF SALBUTAMOL
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [115]
    P-value
    		 < 0.001 [116]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [115] - Active group: The mean was 147.3 (111.0-183.6) and the median 92.0 (40.3-224.0). (Figure 69 and Table 4) Placebo group: The mean was 328.9 (242.4-415.3) and the median 252.5 (120.0-387.0). Hodges-Lehman estimator was -130.0 (-193.0, -65.0)
    [116] - The active group had an improvement of 64% over placebo. The differences between both groups of were significant.
    Statistical analysis title
    		 TOTAL SCORE OF INHALED BUDESONIDE
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [117]
    P-value
    		 < 0.001 [118]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [117] - Active group: The mean was 179.3 (115.9-242.6) and the median 38.0 (0.0-272.0). Placebo group: The mean was 392.5 (296.0-489.1) and the median 323.0 (80.0-539.0). Hodges-Lehman estimator was -185.0 (-282.0, -62.0).
    [118] - The active group had an improvement of 88% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL SCORE OF PREDNISOLONE DROPS
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [119]
    P-value
    		 = 0.002 [120]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [119] - Active group: The mean was 5.3 (3.0-7.7) and the median 0.0 (0.0-8.0). Placebo group: The mean was 12.4 (7.3-17.4) and the median 7.5 (0.0-18.0). Hodges-Lehman estimator was -3.0 (-7.0, 0.0).
    [120] - The active group had an improvement of 100% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 TOTAL SCORE OF MONTELUKAST 4 mg
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [121]
    P-value
    		 = 0.957 [122]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [121] - Active group: The mean was 189.9 (164.7-215.1) and the median 212.5 (129.8-254.0). Placebo group: The mean was 185.4 (157.3-213.6) and the median 206.0 (141.5-257.0). Hodges-Lehman estimator was 0.0 (-30.0, 34.0).
    [122] - The differences between both groups of treatment were not significant.
    Statistical analysis title
    		 TOTAL SCORE OF OTHER MEDICATION
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [123]
    P-value
    		 = 0.333 [124]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [123] - Active group: The mean was 173.6 (100.5-246.8) and the median 58.0 (9.8-213.0). Placebo group: The mean was 191.7 (122.3-261.1) and the median 103.0 (19.0-194.5). Hodges-Lehman estimator was -11.0 (-58.0, 14.0)
    [124] - The active group had an improvement of 44% over placebo. The differences between both groups of treatment were not significant
    Statistical analysis title
    		 TOTAL COMBINATION OF SYMPTOM AND MEDICATION SCORES
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [125]
    P-value
    		 < 0.001 [126]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [125] - Active group: The mean was 1088.3 (922.1-1254.4) and the median 925.0 (584.3-1504.0). Placebo group: The mean was 1760.9 (1505.9-2016.0) and the median 1702.0 (1043.3-2316.3). Hodges-Lehman estimator was -594.0 (-884.0, -308.0).
    [126] - The active group had an improvement of 46% over placebo. The differences between both groups of treatment were significant.

    Secondary: Health resource consumption

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    End point title
    		 Health resource consumption
    End point description
    The unscheduled visits to health centre, emergency service visits, days of hospitalization and cost thereof, complementary tests, phone calls to the doctor or paediatrician were counted per patient.
    End point type
    Secondary
    End point timeframe
    One year
    End point values
    		 Active group Placebo
    Number of subjects analysed
    62
    58
    Units: Percentage
        number (confidence interval 95%)
    13.5 (11.2 to 15.9)
    17.9 (14.7 to 21.1)
    Statistical analysis title
    		 TOTAL HEALTH RESOURCES
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [127]
    P-value
    		 = 0.055 [128]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [127] - Active group: The mean was 13.5 (11.2-15.9) and the median 11.0 (7.0-19.0). Placebo group: The mean was 17.9 (14.7-21.1) and the median 14.5 (10.0-23.0). Hodges-Lehman estimator was -3.0 (-9.0, 0.0)
    [128] - The active group had an improvement of 24% over placebo. The differences between both groups of treatment were not significant.
    Statistical analysis title
    		 DAYS IN THE INTENSIVE CARE UNIT
    Comparison groups
    Placebo v Active group
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [129]
    P-value
    		 = 0.0293 [130]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [129] - Active group: The mean was 0.0 (0.0-0.0) and the median 0.0 (0.0-0.0). Placebo group: The mean was 0.1 (-0.1-0.2) and the median 0.0 (0.0-0.0). Hodges-Lehman estimator was -0.0 (-0.0, 0.0)
    [130] - The active group had no improvement over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 NON-PROGRAMMED VISITS TO PAEDIATRICIAN
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [131]
    P-value
    		 = 0.151 [132]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [131] - Active group: The mean was 8.6 (6.8-10.5) and the median 6.5 (3.3-13.8). Placebo group: The mean was 10.5 (8.5-12.5) and the median 9.5 (4.0-15.0). Hodges-Lehman estimator was -2.0 (-4.0, 1.0)
    [132] - The active group had an improvement of 32% over placebo. The differences between both groups of treatment were not significant.
    Statistical analysis title
    		 NON-PROGRAMMED VISITS TO SPECIALIST
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [133]
    P-value
    		 = 0.15 [134]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [133] - Active group: The mean was 0.5 (0.2-0.7) and the median 0.0 (0.0-0.8). Placebo group: The mean was 0.8 (0.4-1.2) and the median 0.0 (0.0-1.0). Hodges-Lehman estimator was 0.0 (0.0, 0.0)
    [134] - The active group had no improvement over placebo. The differences between both groups of treatment were not significant
    Statistical analysis title
    		 VISITS TO URGENCIES
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [135]
    P-value
    		 = 0.081 [136]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [135] - Active group: The mean was 2.6 (2.0-3.2) and the median 2.0 (1.0-4.0). Placebo group: The mean was 3.9 (3.0-4.9) and the median 3.0 (1.0-5.3). Hodges-Lehman estimator was -1.0 (-2.0, 0.0).
    [136] - The active group had an improvement of 33% over placebo. The differences between both groups of treatment were not significant.
    Statistical analysis title
    		 DAYS OF HOSPITALIZATION
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [137]
    P-value
    		 = 0.916 [138]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [137] - Active group: The mean was 0.7 (0.2-1.3) and the median 0.0 (0.0-0.0). Placebo group: The mean was 0.9 (0.2-1.5) and the median 0.0 (0.0-0.0). Hodges-Lehman estimator was 0.0 (0.0, 0.0)
    [138] - The active group had no improvement over placebo. The differences between both groups of treatment were not significant
    Statistical analysis title
    		 COMPLEMENTARY TESTS
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [139]
    P-value
    		 = 0.61 [140]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [139] - Active group: The mean was 0.7 (0.4-1.0) and the median 0.0 (0.0-1.0). Placebo group: The mean was 0.6 (0.3-0.9) and the median 0.0 (0.0-1.0).
    [140] - The active group had no improvement over placebo. The differences between both groups of treatment were not significant.
    Statistical analysis title
    		 TELEPHONE CALLS TO PEDIATRITIAN
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [141]
    P-value
    		 = 0.025 [142]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [141] - Active group: The mean was 0.4 (0.2-0.6) and the median 0.0 (0.0-0.8). Placebo group: The mean was 1.1 (0.6-1.6) and the median 0.0 (0.0-1.0). Hodges-Lehman estimator was 0.0 (0.0, 0.0).
    [142] - The active group had no improvement over placebo. The differences between both groups of treatment were significant.

    Secondary: Social resources

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    End point title
    		 Social resources
    End point description
    Number of the absenteeism days from nursery, caregivers to the child at home and during hospital admissions per patient.
    End point type
    Secondary
    End point timeframe
    One year
    End point values
    		 Active group Placebo
    Number of subjects analysed
    62
    58
    Units: Percentage
        number (confidence interval 95%)
    23 (5.4 to 40.5)
    24.7 (11.9 to 37.5)
    Statistical analysis title
    		 DAYS OF SCHOOL/KINDERGARTEN ABSENTEEISM
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [143]
    P-value
    		 = 0.031 [144]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [143] - Active group: The mean was 15.4 (6.4-24.3) and the median 4.0 (0.0-17.3). Placebo group: The mean was 19.4 (11.8-27.0) and the median 11.0 (2.0-25.0). Hodges-Lehman estimator was -3.0 (-9.0, 0.0)
    [144] - The active group had an improvement of 64% over placebo. The differences between both groups of treatment were significant.
    Statistical analysis title
    		 CAREGIVERS
    Comparison groups
    Active group v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [145]
    P-value
    		 = 0.04 [146]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [145] - Active group: The mean was 23.0 (5.4-40.5) and the median 5.5 (0.0-19.0). Placebo group: The mean was 24.7 (11.9-37.5) and the median 13.0 (2.0-27.0) Hodges-Lehman estimator was -2.0 (-10.0, 0.0)
    [146] - The active group had an improvement of 58% over placebo. The differences between both groups of treatment were significant.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    One year
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Active
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Active Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Epileptic seizure
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         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: 0%
    Non-serious adverse events
    		 Active Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 61 (59.02%)
    42 / 59 (71.19%)
    Vascular disorders
    Epistaxis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    Surgical and medical procedures
    Adenotonsillectomy
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    General malaise
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 59 (3.39%)
         occurrences all number
    3
    2
    Fatigue
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Heart murmur
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Aphthas
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Immune system disorders
    Hypoglycemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Atopic Eczema
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 59 (3.39%)
         occurrences all number
    2
    2
    Urticaria
         subjects affected / exposed
    2 / 61 (3.28%)
    3 / 59 (5.08%)
         occurrences all number
    2
    3
    Anaphylaxis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Social circumstances
    Stomatitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Apnoea
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Kidney stones
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 59 (3.39%)
         occurrences all number
    1
    2
    Head injury
         subjects affected / exposed
    0 / 61 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    4
    Blood and lymphatic system disorders
    Iron-deficiency anaemia
         subjects affected / exposed
    2 / 61 (3.28%)
    3 / 59 (5.08%)
         occurrences all number
    2
    3
    Adenitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Neutropenia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Corneal ulcer
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 61 (8.20%)
    9 / 59 (15.25%)
         occurrences all number
    6
    11
    Gastroenteritis
         subjects affected / exposed
    5 / 61 (8.20%)
    13 / 59 (22.03%)
         occurrences all number
    5
    16
    Vomiting
         subjects affected / exposed
    2 / 61 (3.28%)
    2 / 59 (3.39%)
         occurrences all number
    2
    3
    Constipation
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    Oral candidiasis
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 59 (0.00%)
         occurrences all number
    3
    0
    Hepatobiliary disorders
    Herpetic Gingivoestomatitis
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    4 / 61 (6.56%)
    9 / 59 (15.25%)
         occurrences all number
    6
    11
    Hand-foot-and-mouth disease
         subjects affected / exposed
    5 / 61 (8.20%)
    1 / 59 (1.69%)
         occurrences all number
    5
    1
    Scarlet fever
         subjects affected / exposed
    3 / 61 (4.92%)
    2 / 59 (3.39%)
         occurrences all number
    3
    3
    Renal and urinary disorders
    Nephrocalcinosis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Pyelonephritis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 59 (3.39%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Synovitis
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 59 (1.69%)
         occurrences all number
    3
    1
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    Cellulitis
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    Chickenpox
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 59 (1.69%)
         occurrences all number
    4
    1
    Conjunctivitis
         subjects affected / exposed
    10 / 61 (16.39%)
    4 / 59 (6.78%)
         occurrences all number
    14
    6
    Herpes Labialis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Facial herpes
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Mononucleosis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Coeliac disease
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Mouth Bleeding
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jun 2013
    Se incluye un centro nuevo para conseguir el tamaño de la muestra establecido en el protocolo y no tener que solicitar una ampliación del periodo de reclutamiento. Este estudio podría revelar que la mejora de inmunidad frente a estos virus se debe a un mecanismo de reconocimiento cruzado: Es concebible que la mejora de la respuesta frente a estos virus en individuos tratados con el producto se traduzca en cambios en la identidad y número (breath) de epítopos específicos de los virus que son reconocidos. Por ello, en este objetivo sintetizaremos epitopos solapantes correspondiente a las proteínas de la capside de una cepa de estos virus y mediante ensayos de producción de citocinas por ELISPOT determinaremos el número e identidad de los péptidos que son reconocidos en los individuos antes y a lo largo de las inmunizaciones. Los péptidos que sean objeto de reconocimiento se compararán con los proteomas de las bacterias incluidas en el producto.
    02 Jan 2015
    El Dr. Rafael Calderón deja de prestar sus servicios en el Hospital de Manises, y por tanto como Investigador Principal del ensayo. El nuevo Investigador Principal será la Dra. Mª José Palao Ortuño. Actualmente la Dra. Palao es Investigador Colaborador de este ensayo y desempeña las mismas funciones que el Investigador Principal. Se amplía el periodo de reclutamiento a 3 años, debido a la imposibilidad de reclutar el nº de sujetos establecidos en el protocolo (120), en el periodo establecido de 2 años. Por ello también se amplía la duración del ensayo un año más.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33705665
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