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    Clinical Trial Results:
    Efficacy of Intermittent Tiotropium in Early Childhood Wheezing

    Summary
    EudraCT number
    		 2015-002985-22
    Trial protocol
    		 FI  
    Global end of trial date
    18 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jan 2023
    First version publication date
    22 Jan 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TFS01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03199976
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mika J. Mäkelä
    Sponsor organisation address
    P.O. Box 160, Helsinki, Finland, FIN-00029 HUS
    Public contact
    Paediatric Unit -- Trials, Department of Allergology, Helsinki University Hospital, +358 94711,
    Scientific contact
    Paediatric Unit -- Trials, Department of Allergology, Helsinki University Hospital, +358 94711,
    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
    14 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Nov 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Nov 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary AIM of the study is 1) to find out the effect of intermittent tiotropium bromide and salbutamol as needed (TBS) versus intermittent fluticasone propionate and salbutamol as needed (FPS), or solely, salbutamol as needed (SA) on episode-free days in infants and toddlers with recurrent episodes of wheeze and/or shortness of breath. Episode-free days are defined as those days during which there are no symptoms of wheeze and/or shortness of breath, no unscheduled medical visits for wheeze and/or shortness of breath, and no use of rescue or supplementary controller medications.
    Protection of trial subjects
    Most of the study visits took place as part of routine outpatient control visits at the nearest hospital, and the study laboratory tests were taken as part of routine laboratory tests during the routine outpatient visits. Occurrence of drug-related adverse events was attempted to be minimized by including the conditions that may increase the risk for drug-related adverse events in the exclusion criteria.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Apr 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Finland: 80
    Worldwide total number of subjects
    80
    EEA total number of subjects
    80
    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)
    53
    Children (2-11 years)
    27
    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 first patient was recruited to the study on April 20, 2016, and the last patient on December 16, 2019. All participants were recruited in the coordinating center, and the coordinating subinvestigator recruited 98% of the study subjects.

    Pre-assignment
    Screening details
    		 170 patients were screened for eligibility -- 4 of those did not meet inclusion criteria and 44 had at least 1 exclusion criterion. 122 children were considered eligible, and 80 of them were enrolled and randomized. Because the interventions were intermittent, the trial did not include a run-in period.

    Period 1
    Period 1 title
    Baseline period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tiotropium Bromide & Salbutamol
    Arm description
    		 Inhaled tiotropium bromide 5 ug once a day, beginning at the onset of an upper respiratory tract infection and continuing for 7 to 14 days as needed, and inhaled salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spiriva Respimat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2.5 ug two doses once a day via an AeroChamber spacer device, beginning at the onset of an upper respiratory tract infection and continuing for 7 to 14 days as needed

    Investigational medicinal product name
    Ventoline Evohaler
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    0.1 mg 2 doses 4 to 6 times a day via an AeroChamber spacer device as needed for wheeze and shortness of breath

    Arm title
    		 Fluticasone Propionate & Salbutamol
    Arm description
    		 Inhaled fluticasone propionate 125 ug twice a day, beginning at the onset of an upper respiratory tract infection and continuing for 7 to 14 days as needed, and inhaled salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Flixotide Evohaler
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    125 ug twice a day via a Babyhaler spacer device, beginning at the onset of an upper respiratory tract infection and continuing for 7 to 14 days as needed

    Investigational medicinal product name
    Ventoline Evohaler
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    0.1 mg 2 doses 4 to 6 times a day via a Babyhaler spacer device as needed for wheeze and shortness of breath

    Arm title
    		 Salbutamol
    Arm description
    		 Inhaled salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ventoline Evohaler
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    0.1 mg 2 doses 4 to 6 times a day via a Babyhaler spacer device as needed for wheeze and shortness of breath

    Number of subjects in period 1
    		Tiotropium Bromide & Salbutamol Fluticasone Propionate & Salbutamol Salbutamol
    Started
    27
    25
    28
    Completed
    23
    18
    14
    Not completed
    4
    7
    14
         Consent withdrawn by subject
    1
    -
    -
         Lost to follow-up
    -
    1
    1
         Lack of efficacy
    3
    6
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tiotropium Bromide & Salbutamol
    Reporting group description
    		 Inhaled tiotropium bromide 5 ug once a day, beginning at the onset of an upper respiratory tract infection and continuing for 7 to 14 days as needed, and inhaled salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath

    Reporting group title
    Fluticasone Propionate & Salbutamol
    Reporting group description
    		 Inhaled fluticasone propionate 125 ug twice a day, beginning at the onset of an upper respiratory tract infection and continuing for 7 to 14 days as needed, and inhaled salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath

    Reporting group title
    Salbutamol
    Reporting group description
    		 Inhaled salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath

    Reporting group values
    		 Tiotropium Bromide & Salbutamol Fluticasone Propionate & Salbutamol Salbutamol Total
    Number of subjects
    		 27 25 28 80
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 21.4 ( 7.0 ) 20.0 ( 6.8 ) 22.1 ( 6.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9 10 28
        Male
    		 18 16 18 52
    Allergic sensitization
    Defined as a specific IgE level of >=0.70 kU/l to food allergens (i.e. milk, egg, wheat, soy bean, cod, peanut), a specific IgE level of >=0.35 kU/l to aeroallegens (i.e. birch, timothy, mugwort, cat, dog, horse, Dermatophagoides pteronyssinus, Cladosporium herbarum), or in case there was no blood specimen drawn, as an earlier skin prick test result with a wheal diameter of >=3 mm to aeroallergens.
    Units: Subjects
        Sensitized
    		 8 12 5 25
        Not sensitized
    		 19 13 23 55
    Short-course glucocorticoid treatment in previous 2 weeks
    Short-course glucocorticoid treatment in previous 2 weeks, i.e. per oral for 1 to 3 days, or inhaled for 1 to 2 weeks.
    Units: Subjects
        Present
    		 3 10 8 21
        Not present
    		 24 15 20 59
    Physician-confirmed episodes of wheeze and/or shortness of breath
    Units: Number of episodes
        median (inter-quartile range (Q1-Q3))
    		 2 (2 to 3) 3 (2 to 3) 3 (2 to 3) -

    End points

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    End points reporting groups
    Reporting group title
    Tiotropium Bromide & Salbutamol
    Reporting group description
    		 Inhaled tiotropium bromide 5 ug once a day, beginning at the onset of an upper respiratory tract infection and continuing for 7 to 14 days as needed, and inhaled salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath

    Reporting group title
    Fluticasone Propionate & Salbutamol
    Reporting group description
    		 Inhaled fluticasone propionate 125 ug twice a day, beginning at the onset of an upper respiratory tract infection and continuing for 7 to 14 days as needed, and inhaled salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath

    Reporting group title
    Salbutamol
    Reporting group description
    		 Inhaled salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath

    Primary: Proportion of episode-free days

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    End point title
    		 Proportion of episode-free days
    End point description
    Episode-free days were defined as the days with no symptoms of wheeze and/or shortness of breath, no unscheduled medical visits for wheeze and/or shortness of breath, and no use of rescue or supplementary controller medications.
    End point type
    Primary
    End point timeframe
    Up to 48 weeks
    End point values
    		 Tiotropium Bromide & Salbutamol Fluticasone Propionate & Salbutamol Salbutamol
    Number of subjects analysed
    26 [1]
    25 [2]
    26 [3]
    Units: percent
        median (inter-quartile range (Q1-Q3))
    97 (93 to 99)
    87 (78 to 93)
    88 (79 to 95)
    Notes
    [1] - Subjects with diary data available were included in the intention-to treat analysis.
    [2] - Subjects with diary data available were included in the intention-to treat analysis.
    [3] - Subjects with diary data available were included in the intention-to treat analysis.
    Statistical analysis title
    		 Primary outcome analysis -- Episode-free days
    Statistical analysis description
    The primary outcome was efficacy, assessed as intention-to treat by comparing the proportion of episode-free days between the treatment groups. Early termination of recruitment lead to re-calculation of power by replacing an assumed SD of 27% with an observed SD of 17% for episode-free days in the Salbutamol group. Calculations allowing a 20% drop-out rate yielded a sample size of 25 children per group; a total number of 80 recruited subjects was considered sufficient for data analyses.
    Comparison groups
    Tiotropium Bromide & Salbutamol v Fluticasone Propionate & Salbutamol v Salbutamol
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.05 [5]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - Bonferroni correction was applied in pairwise analyses by multiplying each P value by 3.
    [5] - P=0.002 between Tiotropium Bromide & Salbutamol and Fluticasone Propionate & Salbutamol groups. P=0.003 between Tiotropium Bromide & Salbutamol and Salbutamol group.

    Secondary: Unscheduled physician visits for wheeze

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    End point title
    		 Unscheduled physician visits for wheeze
    End point description
    Effect of intervention on the number of unscheduled physician visits for episodes of wheeze and/or shortness of breath.
    End point type
    Secondary
    End point timeframe
    Up to 48 weeks
    End point values
    		 Tiotropium Bromide & Salbutamol Fluticasone Propionate & Salbutamol Salbutamol
    Number of subjects analysed
    27 [6]
    25 [7]
    28 [8]
    Units: Number of participants
        Unscheduled physician visits for wheeze
    10
    10
    14
        No unscheduled physician visits for wheeze
    17
    15
    14
    Notes
    [6] - Analysis performed as intention to treat.
    [7] - Analysis performed as intention to treat.
    [8] - Analysis performed as intention to treat.
    Statistical analysis title
    		 Secondary outcome analysis -- Unscheduled visits
    Statistical analysis description
    Bonferroni correction was applied in pairwise analyses by multiplying each P-value by 3.
    Comparison groups
    Tiotropium Bromide & Salbutamol v Fluticasone Propionate & Salbutamol v Salbutamol
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Rescue Medication

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    End point title
    		 Rescue Medication
    End point description
    Effect of intervention on the need for salbutamol.
    End point type
    Secondary
    End point timeframe
    Up to 48 weeks
    End point values
    		 Tiotropium Bromide & Salbutamol Fluticasone Propionate & Salbutamol Salbutamol
    Number of subjects analysed
    26 [9]
    25 [10]
    26 [11]
    Units: Percentage of days
        median (inter-quartile range (Q1-Q3))
    2 (0 to 7)
    13 (6 to 21)
    12 (6 to 20)
    Notes
    [9] - Subjects with diary data available were included in the intention-to-treat analysis.
    [10] - Subjects with diary data available were included in the intention-to-treat analysis.
    [11] - Subjects with diary data available were included in the intention-to-treat analysis.
    Statistical analysis title
    		 Secondary outcome analysis -- Rescue medication
    Statistical analysis description
    Bonferroni correction was applied in pairwise analyses by multiplying each P-value by 3.
    Comparison groups
    Tiotropium Bromide & Salbutamol v Fluticasone Propionate & Salbutamol v Salbutamol
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [12]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [12] - P<0.001 between Tiotropium Bromide & Salbutamol and Fluticasone Propionate groups. P<0.001 between Tiotropium Bromide & Salbutamol and Salbutamol groups.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 48 weeks
    Adverse event reporting additional description
    Adverse events were charted by collecting data from daily diaries and by reviewing the medical records.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ICD coding
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Tiotropium Bromide & Salbutamol
    Reporting group description
    		 Inhaled tiotropium bromide 5 ug once a day, beginning at the onset of an upper respiratory tract infection and continuing for 7 to 14 days as needed, and inhaled salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath

    Reporting group title
    Flixotide Propionate & Salbutamol
    Reporting group description
    		 Inhaled fluticasone propionate 125 ug twice a day, beginning at the onset of an upper respiratory tract infection and continuing for 7 to 14 days as needed, and inhaled salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath

    Reporting group title
    Salbutamol
    Reporting group description
    		 Inhaled salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath

    Serious adverse events
    		 Tiotropium Bromide & Salbutamol Flixotide Propionate & Salbutamol Salbutamol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 27 (14.81%)
    3 / 25 (12.00%)
    3 / 28 (10.71%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Immune system disorders
    Anaphylactic reaction
    Additional description: Anaphylactic reaction to cashew nut
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Enteritis infectious
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 25 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 25 (12.00%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tiotropium Bromide & Salbutamol Flixotide Propionate & Salbutamol Salbutamol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 27 (70.37%)
    22 / 25 (88.00%)
    23 / 28 (82.14%)
    Injury, poisoning and procedural complications
    Contusion
    Additional description: Minor trauma
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 25 (12.00%)
    2 / 28 (7.14%)
         occurrences all number
    2
    4
    2
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 25 (12.00%)
    1 / 28 (3.57%)
         occurrences all number
    1
    3
    1
    Exanthema
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 25 (8.00%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    2
    Infections and infestations
    Otitis media
         subjects affected / exposed
    16 / 27 (59.26%)
    9 / 25 (36.00%)
    12 / 28 (42.86%)
         occurrences all number
    18
    16
    20
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 27 (48.15%)
    13 / 25 (52.00%)
    9 / 28 (32.14%)
         occurrences all number
    20
    16
    16
    Wheezing
         subjects affected / exposed
    7 / 27 (25.93%)
    7 / 25 (28.00%)
    12 / 28 (42.86%)
         occurrences all number
    10
    12
    19
    Enteritis infectious
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 25 (12.00%)
    2 / 28 (7.14%)
         occurrences all number
    3
    4
    3
    Pharyngitis
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 25 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    2
    0
    2
    Tonsillitis
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 25 (4.00%)
    3 / 28 (10.71%)
         occurrences all number
    1
    1
    3
    Conjunctivitis
         subjects affected / exposed
    4 / 27 (14.81%)
    1 / 25 (4.00%)
    7 / 28 (25.00%)
         occurrences all number
    5
    1
    8
    Laryngitis
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 25 (4.00%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Early termination leading to small numbers of subjects analyzed.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35942814
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