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    Clinical Trial Results:
    Parent-determined oral montelukast therapy for preschool wheeze with stratification for arachidonate-5-lipoxygenase (ALOX5) promoter genotype.

    Summary
    EudraCT number
    		 2009-015626-11
    Trial protocol
    		 GB  
    Global end of trial date
    31 Oct 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Aug 2017
    First version publication date
    27 Aug 2017
    Other versions
    Summary report(s)
    		 EME Report - WAIT Study
    Main Publication
    Qualitative Paper

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    006983 QM
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01142505
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 NIHR-EME Project Number: 08/43/03, NHS Research Ethics Committee Number: 09/H1102/110
    Sponsors
    Sponsor organisation name
    Joint Research management Office, Queen mary Innovation Centre
    Sponsor organisation address
    2 Walden Street, London, United Kingdom, E1 2EF
    Public contact
    Dr Chinedu Nwokoro, Centre for Paediatrics, Blizard Institute Queen Mary University of London, 0207 8822195, c.nwokoro@qmul.ac.uk
    Scientific contact
    Dr Chinedu Nwokoro, Centre for Paediatrics, Blizard Institute Queen Mary University of London, 0207 8822195, c.nwokoro@qmul.ac.uk
    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
    31 Jan 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The principal objective of this research is to determine whether intermittent parent-initiated treatment with oral montelukast in preschool children with a history of wheeze, reduces the need for unscheduled medical attention for wheeze. To assess this treatment will be started by parents or guardians i) at the onset of every cold and continued for a minimum of 7 days or until wheeze has resolved for 48 hours, and ii) for every episode of wheeze not associated with a viral cold, and stopped when symptoms have resolved for 48 hours. For each child, the trial will last 12 months.
    Protection of trial subjects
    Study was conducted under auspices of an IDMC, and the NHS Research Ethics Committee. All subjects were recruited by their treating medical physician. The investigational medicinal product is already in full licensed use for the indication under study. There were no painful interventions involved in the study.
    Background therapy
    		 Children were under standard treatment for asthma and wheezing disease such as inhaled steroids or beta agonist. These were not imposed as part of study protocol.
    Evidence for comparator
    		 This information is included in the study design section of the report. The comparator was an identical placebo, while the IMP was a known drug used in paediatric asthma.
    Actual start date of recruitment
    01 Oct 2010
    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
    United Kingdom: 1346
    Worldwide total number of subjects
    1346
    EEA total number of subjects
    1346
    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)
    463
    Children (2-11 years)
    883
    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
    		 Participants were identified in primary and secondary care centres. Recruitment was planned to encompass only three secondary care centres (the Royal London Hospital, University Hospital Leicester and the Royal Aberdeen Children’s Hospital), but increased to 41 secondary care centres in England and Scotland. Recruitment spanned Oct 2010 to Dec 2012

    Pre-assignment
    Screening details
    		 Eligibility: 10m-5y, >1 wheeze attacks, 1 medically validated, 1 in prev 3m. Exclusions: respiratory comorbidities, sickle cell, BPD, severe developmental delay, montelukast use, other recent trial involvement. 1883 screened, 525 did not ultimately consent, 11 subsequently refused permission for data use, 1 provided no data --> 1346.

    Pre-assignment period milestones
    Number of subjects started
    		 1883 [1]
    Intermediate milestone: Number of subjects
    Consent: 1366
    Intermediate milestone: Number of subjects
    Randomisation: 1358
    Number of subjects completed
    		 1346

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Refused consent: 517
    Reason: Number of subjects
    		 No data collected: 1
    Reason: Number of subjects
    		 Withdrew prior to randomisation: 8
    Reason: Number of subjects
    		 Withdrew permission to use collected data: 11
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: This number (1883) includes all those approached to enter the study.
    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, Data analyst, Carer, Assessor
    Blinding implementation details
    Novalabs (the primary IMP producer) produced a corresponding randomisation code denoting whether a given IMP box contained active medication or placebo. This was kept sealed and held only by the clinical trials pharmacist and a member of the Independent Data and Safety Monitoring Committee (DSMC), in this way all other clinical investigators and participants remained blinded to treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active Treatment
    Arm description
    		 Subjects allocated to active treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Singulair granules
    Investigational medicinal product code
    ATC code: R03DC03
    Other name
    Montelukast
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    IMP was presented as white granules administered either directly into the child’s mouth, or mixed with a spoonful of cold or room temperature soft food. The IMP was used according to the primary manufacturer’s instructions. Specifically, parents were advised not to open the sachet containing the granules until ready to use. After opening the sachet, the full dose of granules was administered within 15 minutes. If mixed with food, the granules must not be stored for future use. The granules were not intended to be dissolved in liquid for administration however liquids could be taken subsequent to administration. The granules were administered without regard to the timing of food ingestion. The dose was one 4mg sachet per day, started at the start of a viral cold or had wheeze, and stopped after 10 days. Children could start a 2nd course should the wheeze persist. If a child vomited after receiving IMP no additional dose was given, and parents recorded this on the diary card.

    Arm title
    		 Placebo
    Arm description
    		 Subjects allocated to receive placebo during the study
    Arm type
    		 Placebo

    Investigational medicinal product name
    Mannitol EP (Pearlitol SD 200)
    Investigational medicinal product code
    N/A
    Other name
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    IMP was presented as white granules administered either directly into the child’s mouth, or mixed with a spoonful of cold or room temperature soft food. The IMP was used according to the primary manufacturer’s instructions. Specifically, parents were advised not to open the sachet containing the granules until ready to use. After opening the sachet, the full dose of granules was administered within 15 minutes. If mixed with food, the granules must not be stored for future use. The granules were not intended to be dissolved in liquid for administration however liquids could be taken subsequent to administration. The granules were administered without regard to the timing of food ingestion. The dose was one 4mg sachet per day, started at the start of a viral cold or had wheeze, and stopped after 10 days. Children could start a 2nd course should the wheeze persist. If a child vomited after receiving IMP no additional dose was given, and parents recorded this on the diary card.

    Number of subjects in period 1
    		Active Treatment Placebo
    Started
    669
    677
    T1 - First Phonecall
    652
    656
    T2 - Second Phonecall
    631
    636
    T3 - Third Phonecall
    616
    624
    T4 - Fourth Phonecall
    604
    605
    T5 - Fifth Phonecall
    591
    590
    T6 - Sixth Phonecall (End of Trial)
    579
    575
    Completed
    579
    575
    Not completed
    90
    102
         Physician decision
    51
    -
         Poor Adherence
    5
    2
         Adverse event, non-fatal
    2
    6
         Other
    17
    -
         Not specified
    -
    37
         Lost to follow-up
    -
    36
         Lack of efficacy
    1
    8
         Protocol deviation
    14
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active Treatment
    Reporting group description
    		 Subjects allocated to active treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects allocated to receive placebo during the study

    Reporting group values
    		 Active Treatment Placebo Total
    Number of subjects
    		 669 677 1346
    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
    Age at date of first IMP dispensing.
    Units: years
        arithmetic mean (standard deviation)
    		 2.6 ± 1.1 2.7 ± 1.1 -
    Gender categorical
    Gender.
    Units: Subjects
        Female
    		 243 240 483
        Male
    		 426 437 863
    Ethnicity
    Self-reported ethnicity
    Units: Subjects
        White
    		 514 512 1026
        Black
    		 19 18 37
        Asian
    		 92 104 196
        Other
    		 44 43 87
    Preterm birth
    Gestation at birth
    Units: Subjects
        <37 weeks
    		 98 98 196
        >37= weeks
    		 571 579 1150
    Birthweight
    Birthweight
    Units: Subjects
        <2500g
    		 79 70 149
        >= 2500g
    		 590 607 1197
    Food Allergy
    Parent-reported food allergy status
    Units: Subjects
        Yes
    		 108 111 219
        No
    		 561 566 1127
    Drug Allergy
    Patient-recorded drug allergy
    Units: Subjects
        Yes
    		 38 42 80
        No
    		 631 635 1266
    Eczema
    Subjects who have ever had eczema.
    Units: Subjects
        Yes
    		 328 349 677
        No
    		 341 328 669
    Maternal Asthma History
    History of asthma in mother (self-report)
    Units: Subjects
        Yes
    		 251 230 481
        No
    		 418 447 865
    Paternal Asthma History
    Paternal asthma history - self-reported
    Units: Subjects
        Yes
    		 199 207 406
        No
    		 470 470 940
    Multitrigger Wheeze
    Parent-reported multiple trigger wheeze
    Units: Subjects
        Yes
    		 192 191 383
        No
    		 477 486 963
    Continuous Inhaled Steroids at study entry
    Subjects on continuous inhaled steroids at study entry.
    Units: Subjects
        Yes
    		 184 213 397
        No
    		 485 464 949
    Historic Hospital Admissions
    Number of hospital admissions for wheeze in preceding 12 months
    Units: Subjects
        >1
    		 579 554 1133
        <=1
    		 90 123 213
    Weight
    Weight at recruitment
    Units: kg
        arithmetic mean (standard deviation)
    		 14 ± 3.3 14.2 ± 3.5 -
    Height
    Height at consent to study
    Units: cm
        arithmetic mean (standard deviation)
    		 89.9 ± 10.4 90.6 ± 11 -
    Age at first wheeze
    Age at first wheeze - parental reported
    Units: Months
        arithmetic mean (standard deviation)
    		 12.8 ± 10.1 12.9 ± 10.8 -
    Interval between onset of URTI and wheezing
    Onset of URTI to onset of wheezing
    Units: Hours
        arithmetic mean (standard deviation)
    		 30.5 ± 26.6 27.7 ± 24.4 -
    Historic Oral corticosteroid courses
    Oral corticosteroid courses taken in preceding 12 months
    Units: Courses
        arithmetic mean (standard deviation)
    		 1.9 ± 1.8 1.9 ± 2 -
    Historic Unscheduled Medical Attendances (USMA)
    USMA in preceding year
    Units: Attendances
        arithmetic mean (standard deviation)
    		 5.4 ± 4.2 5.6 ± 5.1 -
    Subject analysis sets

    Subject analysis set title
    5/5 ALOX5 stratum - active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with 5/5 ALOX5 promoter genotype who were allocated to active medication

    Subject analysis set title
    5/x + x/y stratum - active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with 5/x or x/y ALOX5 promoter genotype who were allocated to active medication

    Subject analysis set title
    5/5 ALOX5 stratum - placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with 5/5 ALOX5 promoter genotype who were allocated to placebo medication

    Subject analysis set title
    5/x + x/y stratum - placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with 5/x + x/y ALOX5 promoter genotype who were allocated to active medication

    Subject analysis set title
    ICS - Active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Children receiving inhaled corticosteroid and randomised to receive montelukast

    Subject analysis set title
    ICS - Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Children receiving inhaled corticosteroids at baseline and randomised to receive placebo

    Subject analysis set title
    No ICS - Active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Children not on ICS at baseline and randomised to montelukast

    Subject analysis set title
    No ICS - Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects not on inhaled corticosteroids at baseline and randomised to placebo medication

    Subject analysis set title
    5/5 + 5/x stratum - active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with 5/5 or 5/x ALOX5 promoter genotype who were allocated to active medication

    Subject analysis set title
    x/y stratum - Active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with x/y ALOX5 promoter genotype who were allocated to active medication

    Subject analysis set title
    5/5 + 5/x stratum - placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with 5/5 or 5/x ALOX5 promoter genotype who were allocated to placebo medication

    Subject analysis set title
    x/y stratum - placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects with x/y ALOX5 promoter genotype who were allocated to placebo medication

    Subject analysis set title
    Multi trigger wheeze - active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with multi trigger wheeze allocated to montelukast

    Subject analysis set title
    Multi trigger wheeze - placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with multi trigger wheeze allocated to placebo medication

    Subject analysis set title
    Episodic viral wheeze - active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with episodic viral wheeze allocated to montelukast

    Subject analysis set title
    Episodic viral wheeze - placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with episodic viral wheeze allocated to placebo medication

    Subject analysis sets values
    		 5/5 ALOX5 stratum - active 5/x + x/y stratum - active 5/5 ALOX5 stratum - placebo 5/x + x/y stratum - placebo ICS - Active ICS - Placebo No ICS - Active No ICS - Placebo 5/5 + 5/x stratum - active x/y stratum - Active 5/5 + 5/x stratum - placebo x/y stratum - placebo Multi trigger wheeze - active Multi trigger wheeze - placebo Episodic viral wheeze - active Episodic viral wheeze - placebo
    Number of subjects
    416
    253
    426
    251
    276
    282
    376
    374
    627
    25
    622
    34
    190
    183
    462
    473
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Age at date of first IMP dispensing.
    Units: years
        arithmetic mean (standard deviation)
    2.6 ± 1.1
    2.5 ± 1.1
    2.6 ± 1.1
    2.8 ± 1.2
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Gender categorical
    Gender.
    Units: Subjects
        Female
    154
    89
    150
    90
        Male
    262
    164
    276
    161
    Ethnicity
    Self-reported ethnicity
    Units: Subjects
        White
    335
    179
    338
    174
        Black
    5
    14
    4
    14
        Asian
    55
    37
    58
    46
        Other
    21
    23
    26
    17
    Preterm birth
    Gestation at birth
    Units: Subjects
        <37 weeks
    58
    40
    56
    42
        >37= weeks
    358
    213
    370
    209
    Birthweight
    Birthweight
    Units: Subjects
        <2500g
    51
    28
    42
    28
        >= 2500g
    365
    225
    384
    223
    Food Allergy
    Parent-reported food allergy status
    Units: Subjects
        Yes
    64
    44
    64
    47
        No
    352
    209
    362
    204
    Drug Allergy
    Patient-recorded drug allergy
    Units: Subjects
        Yes
    26
    12
    23
    29
        No
    390
    241
    403
    222
    Eczema
    Subjects who have ever had eczema.
    Units: Subjects
        Yes
    207
    121
    215
    134
        No
    209
    132
    211
    117
    Maternal Asthma History
    History of asthma in mother (self-report)
    Units: Subjects
        Yes
    156
    95
    141
    89
        No
    260
    158
    285
    162
    Paternal Asthma History
    Paternal asthma history - self-reported
    Units: Subjects
        Yes
    126
    73
    126
    81
        No
    290
    180
    300
    170
    Multitrigger Wheeze
    Parent-reported multiple trigger wheeze
    Units: Subjects
        Yes
    120
    72
    131
    60
        No
    296
    181
    295
    191
    Continuous Inhaled Steroids at study entry
    Subjects on continuous inhaled steroids at study entry.
    Units: Subjects
        Yes
    118
    66
    144
    69
        No
    198
    187
    282
    182
    Historic Hospital Admissions
    Number of hospital admissions for wheeze in preceding 12 months
    Units: Subjects
        >1
    363
    216
    351
    203
        <=1
    53
    37
    75
    48
    Weight
    Weight at recruitment
    Units: kg
        arithmetic mean (standard deviation)
    14 ± 3
    13.9 ± 3.7
    14 ± 3.3
    14.6 ± 3.8
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Height
    Height at consent to study
    Units: cm
        arithmetic mean (standard deviation)
    90 ± 10.3
    89.8 ± 10.5
    89.9 ± 10.5
    91.8 ± 11.7
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Age at first wheeze
    Age at first wheeze - parental reported
    Units: Months
        arithmetic mean (standard deviation)
    12.4 ± 9.8
    13.5 ± 10.5
    12.4 ± 10.4
    13.6 ± 11.5
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Interval between onset of URTI and wheezing
    Onset of URTI to onset of wheezing
    Units: Hours
        arithmetic mean (standard deviation)
    31.6 ± 27.4
    28.8 ± 25.2
    27.3 ± 23.4
    28.2 ± 26
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Historic Oral corticosteroid courses
    Oral corticosteroid courses taken in preceding 12 months
    Units: Courses
        arithmetic mean (standard deviation)
    2 ± 1.9
    1.8 ± 1.8
    1.9 ± 1.9
    1.8 ± 2
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Historic Unscheduled Medical Attendances (USMA)
    USMA in preceding year
    Units: Attendances
        arithmetic mean (standard deviation)
    5.5 ± 4.3
    5.4 ± 4.1
    5.7 ± 5.3
    5.6 ± 4.6
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±

    End points

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    End points reporting groups
    Reporting group title
    Active Treatment
    Reporting group description
    		 Subjects allocated to active treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects allocated to receive placebo during the study

    Subject analysis set title
    5/5 ALOX5 stratum - active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with 5/5 ALOX5 promoter genotype who were allocated to active medication

    Subject analysis set title
    5/x + x/y stratum - active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with 5/x or x/y ALOX5 promoter genotype who were allocated to active medication

    Subject analysis set title
    5/5 ALOX5 stratum - placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with 5/5 ALOX5 promoter genotype who were allocated to placebo medication

    Subject analysis set title
    5/x + x/y stratum - placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with 5/x + x/y ALOX5 promoter genotype who were allocated to active medication

    Subject analysis set title
    ICS - Active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Children receiving inhaled corticosteroid and randomised to receive montelukast

    Subject analysis set title
    ICS - Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Children receiving inhaled corticosteroids at baseline and randomised to receive placebo

    Subject analysis set title
    No ICS - Active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Children not on ICS at baseline and randomised to montelukast

    Subject analysis set title
    No ICS - Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects not on inhaled corticosteroids at baseline and randomised to placebo medication

    Subject analysis set title
    5/5 + 5/x stratum - active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with 5/5 or 5/x ALOX5 promoter genotype who were allocated to active medication

    Subject analysis set title
    x/y stratum - Active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with x/y ALOX5 promoter genotype who were allocated to active medication

    Subject analysis set title
    5/5 + 5/x stratum - placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with 5/5 or 5/x ALOX5 promoter genotype who were allocated to placebo medication

    Subject analysis set title
    x/y stratum - placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects with x/y ALOX5 promoter genotype who were allocated to placebo medication

    Subject analysis set title
    Multi trigger wheeze - active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with multi trigger wheeze allocated to montelukast

    Subject analysis set title
    Multi trigger wheeze - placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with multi trigger wheeze allocated to placebo medication

    Subject analysis set title
    Episodic viral wheeze - active
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with episodic viral wheeze allocated to montelukast

    Subject analysis set title
    Episodic viral wheeze - placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with episodic viral wheeze allocated to placebo medication

    Primary: Unscheduled Medical Attendances (USMA) per subject per year

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    End point title
    		 Unscheduled Medical Attendances (USMA) per subject per year
    End point description
    The number of times a child attends for an unscheduled medical opinion (a summation of hospital admissions, attendances, GP visits,) with respiratory problems over a 12 month period as confirmed from clinical records
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Active Treatment Placebo 5/5 ALOX5 stratum - active 5/x + x/y stratum - active 5/5 ALOX5 stratum - placebo 5/x + x/y stratum - placebo ICS - Active ICS - Placebo No ICS - Active No ICS - Placebo 5/5 + 5/x stratum - active x/y stratum - Active 5/5 + 5/x stratum - placebo x/y stratum - placebo Multi trigger wheeze - active Multi trigger wheeze - placebo Episodic viral wheeze - active Episodic viral wheeze - placebo
    Number of subjects analysed
    652 [1]
    656 [2]
    404
    248
    410
    246
    274
    282
    373
    368
    623
    24
    616
    34
    188
    183
    459
    467
    Units: USMA/subject
        arithmetic mean (standard deviation)
    2 ± 2.6
    2.3 ± 2.7
    2 ± 2.7
    2 ± 2.5
    2.4 ± 3
    2 ± 2.3
    2 ± 3
    2 ± 2.3
    2 ± 2.2
    2.5 ± 3
    2 ± 2.6
    1.7 ± 1.8
    2.3 ± 2.8
    1.9 ± 2
    2.1 ± 3
    2 ± 2.5
    2 ± 2.4
    2.3 ± 2.9
    Attachments
    		 Forest Plot of Primary Outcome incl Stratum
    Notes
    [1] - Previously explained.
    [2] - Previously explained
    Statistical analysis title
    		 USMA: Montelukast vs Placebo - unstratified
    Statistical analysis description
    Unscheduled Medical Attendances in Montelukast-treated subjects compared with Placebo-treated subjects.
    Comparison groups
    Active Treatment v Placebo
    Number of subjects included in analysis
    1308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.06
    Method
    		 Poisson Regression
    Parameter type
    		 Incidence Rate Ratio
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.01
    Variability estimate
    Standard deviation
    Notes
    [3] - Data are analysed using Poisson regression with fixed effects for stratification factor and treatment group, a random effect for individual to account for overdispersion with follow up time fitted as the exposure. Follow up time is based on time from randomisation until either 12 month end of trial date or date of last phonecall. Primary outcome data is taken from the phonecall which occurred every two months, and confirmed from diary cards and primary and secondary care records.
    Statistical analysis title
    		 USMA: Montelukast vs Placebo (5/5)
    Statistical analysis description
    Unscheduled Medical Attendances in Montelukast-treated subjects compared with Placebo-treated subjects in the 5/5 promoter polymorphism genotype arm.
    Comparison groups
    5/5 ALOX5 stratum - active v 5/5 ALOX5 stratum - placebo
    Number of subjects included in analysis
    814
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.01 [5]
    Method
    		 Poisson Regression
    Parameter type
    		 Incidence Rate Ratio
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 0.95
    Variability estimate
    Standard deviation
    Notes
    [4] - Data are analysed using Poisson regression with fixed effects for stratification factor and treatment group, a random effect for individual to account for overdispersion with follow up time fitted as the exposure. Follow up time is based on time from randomisation until either 12 month end of trial date or date of last phonecall. Primary outcome data is taken from the phonecall which occurred every two months, and confirmed from diary cards and primary and secondary care records.
    [5] - P-value for interaction between genotype and treatment is 0.08 (non-significant).
    Statistical analysis title
    		 USMA:Montelukast vs Placebo [5/x + x/y]
    Statistical analysis description
    Unscheduled Medical Attendances in Montelukast-treated subjects compared with Placebo-treated subjects in the [5/x + x/y] promoter polymorphism genotype arm.
    Comparison groups
    5/x + x/y stratum - active v 5/x + x/y stratum - placebo
    Number of subjects included in analysis
    494
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.79 [7]
    Method
    		 Poisson Regression
    Parameter type
    		 Incidence Rate Ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.29
    Variability estimate
    Standard deviation
    Notes
    [6] - Data are analysed using Poisson regression with fixed effects for stratification factor and treatment group, a random effect for individual to account for overdispersion with follow up time fitted as the exposure. Follow up time is based on time from randomisation until either 12 month end of trial date or date of last phonecall. Primary outcome data is taken from the phonecall which occurred every two months, and confirmed from diary cards and primary and secondary care records.
    [7] - P-value for the interaction of genotype (5/5 vs [5/x +x/y])with the primary outcome = 0.08 (non-significant).
    Statistical analysis title
    		 USMA: Montelukast vs Placebo (5/5 + 5/x)
    Statistical analysis description
    Unscheduled Medical Attendances in Montelukast-treated subjects compared with Placebo-treated subjects in the (5/5 + 5/x) promoter polymorphism genotype arm.
    Comparison groups
    5/5 + 5/x stratum - active v 5/5 + 5/x stratum - placebo v x/y stratum - Active v x/y stratum - placebo
    Number of subjects included in analysis
    1297
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.93 [9]
    Method
    		 Poisson Regression
    Parameter type
    		 Incidence Rate Ratio in each arm
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [8] - Data are analysed using Poisson regression with fixed effects for stratification factor and treatment group, a random effect for individual to account for overdispersion with follow up time fitted as the exposure. Follow up time is based on time from randomisation until either 12 month end of trial date or date of last phonecall. Primary outcome data is taken from the phonecall which occurred every two months, and confirmed from diary cards and primary and secondary care records.
    [9] - P-value for interaction between genotype and treatment is 0.93 (non-significant).
    Statistical analysis title
    		 USMA: Montelukast vs Placebo (x/y)
    Statistical analysis description
    Unscheduled Medical Attendances in Montelukast-treated subjects compared with Placebo-treated subjects in the (x/y) promoter polymorphism genotype arm.
    Comparison groups
    5/5 + 5/x stratum - active v 5/5 + 5/x stratum - placebo v x/y stratum - Active v x/y stratum - placebo
    Number of subjects included in analysis
    1297
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.93 [11]
    Method
    		 Poisson Regression
    Parameter type
    		 Incidence Rate Ratio in each arm
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [10] - Data are analysed using Poisson regression with fixed effects for stratification factor and treatment group, a random effect for individual to account for overdispersion with follow up time fitted as the exposure. Follow up time is based on time from randomisation until either 12 month end of trial date or date of last phonecall. Primary outcome data is taken from the phonecall which occurred every two months, and confirmed from diary cards and primary and secondary care records.
    [11] - P-value for interaction between genotype and treatment is 0.93 (non-significant).
    Statistical analysis title
    		 USMA: Montelukast vs Placebo (ICS at baseline)
    Statistical analysis description
    Unscheduled Medical Attendances in Montelukast-treated subjects compared with Placebo-treated subjects in children with or without Inhaled Corticosteroids (ICS) at baseline.
    Comparison groups
    ICS - Active v ICS - Placebo v No ICS - Active v No ICS - Placebo
    Number of subjects included in analysis
    1297
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.09 [13]
    Method
    		 Poisson Regression
    Parameter type
    		 Incidence Rate Ratio in each arm
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [12] - Data are analysed using Poisson regression with fixed effects for stratification factor and treatment group, a random effect for individual to account for overdispersion with follow up time fitted as the exposure. Follow up time is based on time from randomisation until either 12 month end of trial date or date of last phonecall. Primary outcome data is taken from the phonecall which occurred every two months, and confirmed from diary cards and primary and secondary care records.
    [13] - P-value for interaction between inhaled steroid use and treatment is 0.09 (non-significant).
    Statistical analysis title
    		 USMA: Montelukast vs Placebo (MTW vs EVW)
    Statistical analysis description
    Unscheduled Medical Attendances in Montelukast-treated subjects compared with Placebo-treated subjects in children with multiple trigger wheeze (MTW) vs Episodic Viral Wheeze (EVW) at baseline.
    Comparison groups
    Multi trigger wheeze - active v Multi trigger wheeze - placebo v Episodic viral wheeze - active v Episodic viral wheeze - placebo
    Number of subjects included in analysis
    1297
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.19 [15]
    Method
    		 Poisson Regression
    Parameter type
    		 Incidence Rate Ratio in each arm
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [14] - Data are analysed using Poisson regression with fixed effects for stratification factor and treatment group, a random effect for individual to account for overdispersion with follow up time fitted as the exposure. Follow up time is based on time from randomisation until either 12 month end of trial date or date of last phonecall. Primary outcome data is taken from the phonecall which occurred every two months, and confirmed from diary cards and primary and secondary care records.
    [15] - P-value for interaction between wheeze phenotype (EVW vs MTW) and treatment is 0.19 (non-significant).

    Secondary: Subjects with one or more unscheduled medical attendances

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    End point title
    		 Subjects with one or more unscheduled medical attendances
    End point description
    Subjects with one or more USMA
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Active Treatment Placebo
    Number of subjects analysed
    652 [16]
    656 [17]
    Units: Subjects
    426
    456
    Notes
    [16] - Intention to treat population
    [17] - Intention to treat population
    Statistical analysis title
    		 Children with one or more USMA by active/placebo
    Statistical analysis description
    Data are analysed using Poisson regression with fixed effects for stratification factor and treatment group, a random effect for individual to account for overdispersion with follow up time fitted as the exposure. Follow up time is based on time from randomisation until either 12 month end of trial date or date of last phonecall. Primary outcome data is taken from the phonecall which occurred every two months, and confirmed from diary cards and primary and secondary care records.
    Comparison groups
    Active Treatment v Placebo
    Number of subjects included in analysis
    1308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1 [18]
    Method
    		 Poisson Regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.04
    Notes
    [18] - Non-significant

    Secondary: Time to first unscheduled medical attendance

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    End point title
    		 Time to first unscheduled medical attendance
    End point description
    Time to first unscheduled medical attendance.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Active Treatment Placebo
    Number of subjects analysed
    652 [19]
    656 [20]
    Units: days
    147
    130
    Attachments
    		 Kaplan-Meier Curves
    Notes
    [19] - Intention to treat population
    [20] - Time to first unscheduled medical attendance in days
    Statistical analysis title
    		 Time to first USMA by active/placebo
    Statistical analysis description
    Data are analysed using Poisson regression with fixed effects for stratification factor and treatment group, a random effect for individual to account for overdispersion with follow up time fitted as the exposure. Follow up time is based on time from randomisation until either 12 month end of trial date or date of last phonecall. Primary outcome data is taken from the phonecall which occurred every two months, and confirmed from diary cards and primary and secondary care records.
    Comparison groups
    Active Treatment v Placebo
    Number of subjects included in analysis
    1308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09 [21]
    Method
    		 Poisson regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.02
    Notes
    [21] - Non-significant

    Secondary: Need for rescue oral corticosteroids

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    End point title
    		 Need for rescue oral corticosteroids
    End point description
    Data are analysed using Poisson regression with fixed effects for stratification factor and treatment group, a random effect for individual to account for overdispersion with follow up time fitted as the exposure. Follow up time is based on time from randomisation until either 12 month end of trial date or date of last phonecall. Primary outcome data is taken from the phonecall which occurred every two months, and confirmed from diary cards and primary and secondary care records.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Active Treatment Placebo
    Number of subjects analysed
    652 [22]
    656 [23]
    Units: Courses/child
        arithmetic mean (standard deviation)
    0.26 ± 0.7
    0.33 ± 0.9
    Notes
    [22] - ITT population
    [23] - ITT population
    Statistical analysis title
    		 Need for oral corticosteroids in follow-up
    Comparison groups
    Active Treatment v Placebo
    Number of subjects included in analysis
    1308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03 [24]
    Method
    		 Poisson regression
    Parameter type
    		 Incidence Rate Ratio
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 0.98
    Notes
    [24] - Significant

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reportable for one year from the point of trial entry
    Adverse event reporting additional description
    Adverse events were reported on the diary card completed during courses of IMP and sent to the lead centre, reported in the two-monthly telephone questionnaire completed throughout follow-up, or reported as they occurred by telephone to the local research nurse. They were analysed by the local Principal Investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 No dictionary
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Active Treatment
    Reporting group description
    		 Subjects allocated to active treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects allocated to receive placebo during the study

    Serious adverse events
    		 Active Treatment Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 669 (0.00%)
    1 / 677 (0.15%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Skin and subcutaneous tissue disorders
    Cutaneous
         subjects affected / exposed
    0 / 669 (0.00%)
    1 / 677 (0.15%)
         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 Treatment Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    197 / 669 (29.45%)
    235 / 677 (34.71%)
    Injury, poisoning and procedural complications
    Minor Injury
    Additional description: Number of subjects affected is unknown, only number of occurrences. For purposes of data entry presumption of one occurrence per subject is made.
         subjects affected / exposed
    27 / 669 (4.04%)
    22 / 677 (3.25%)
         occurrences all number
    27
    22
    Major Injury
    Additional description: Number of subjects affected is unknown, only number of occurrences. For purposes of data entry presumption of one occurrence per subject is made.
         subjects affected / exposed
    2 / 669 (0.30%)
    1 / 677 (0.15%)
         occurrences all number
    2
    1
    Nervous system disorders
    Central nervous system
    Additional description: Number of subjects affected is unknown, only number of occurrences. For purposes of data entry presumption of one occurrence per subject is made.
         subjects affected / exposed
    25 / 669 (3.74%)
    46 / 677 (6.79%)
         occurrences all number
    25
    46
    Blood and lymphatic system disorders
    Haematological
    Additional description: Number of subjects affected is unknown, only number of occurrences. For purposes of data entry presumption of one occurrence per subject is made.
         subjects affected / exposed
    5 / 669 (0.75%)
    7 / 677 (1.03%)
         occurrences all number
    5
    7
    Immune system disorders
    Allergy
    Additional description: Number of subjects affected is unknown, only number of occurrences. For purposes of data entry presumption of one occurrence per subject is made.
         subjects affected / exposed
    16 / 669 (2.39%)
    20 / 677 (2.95%)
         occurrences all number
    16
    20
    Gastrointestinal disorders
    Gastrointestinal
    Additional description: Any GI disturbance Number of subjects affected is unknown, only number of occurrences. For purposes of data entry presumption of one occurrence per subject is made.
         subjects affected / exposed
    86 / 669 (12.86%)
    122 / 677 (18.02%)
         occurrences all number
    86
    122
    Respiratory, thoracic and mediastinal disorders
    Respiratory
    Additional description: Number of subjects affected is unknown, only number of occurrences. For purposes of data entry presumption of one occurrence per subject is made.
         subjects affected / exposed
    34 / 669 (5.08%)
    54 / 677 (7.98%)
         occurrences all number
    34
    54
    Skin and subcutaneous tissue disorders
    Cutaneous
    Additional description: Number of subjects affected is unknown, only number of occurrences. For purposes of data entry presumption of one occurrence per subject is made.
         subjects affected / exposed
    32 / 669 (4.78%)
    53 / 677 (7.83%)
         occurrences all number
    32
    53
    Renal and urinary disorders
    Genitourinary
    Additional description: Number of subjects affected is unknown, only number of occurrences. For purposes of data entry presumption of one occurrence per subject is made.
         subjects affected / exposed
    10 / 669 (1.49%)
    6 / 677 (0.89%)
         occurrences all number
    10
    6
    Musculoskeletal and connective tissue disorders
    Musculoskeletal
    Additional description: Number of subjects affected is unknown, only number of occurrences. For purposes of data entry presumption of one occurrence per subject is made.
         subjects affected / exposed
    0 / 669 (0.00%)
    1 / 677 (0.15%)
         occurrences all number
    0
    1
    Infections and infestations
    Upper respiratory tract infection
    Additional description: Number of subjects affected is unknown, only number of occurrences. For purposes of data entry presumption of one occurrence per subject is made.
         subjects affected / exposed
    73 / 669 (10.91%)
    103 / 677 (15.21%)
         occurrences all number
    73
    103
    Minor infection
    Additional description: Number of subjects affected is unknown, only number of occurrences. For purposes of data entry presumption of one occurrence per subject is made.
         subjects affected / exposed
    87 / 669 (13.00%)
    107 / 677 (15.81%)
         occurrences all number
    87
    107

    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.
    Nil

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26632627
    http://www.ncbi.nlm.nih.gov/pubmed/25212745
    http://www.ncbi.nlm.nih.gov/pubmed/23572193
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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