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    Clinical Trial Results:
    B.R.E.A.T.H.E. Bronchiolitis RCT: Emergency Assisted Therapy with Heliox - an Evaluation. A Prospective, Double-Blinded, Randomised, Controlled Clinical Trial to assess the effect of helium-oxygen gas mixtures during the management of bronchiolitis.

    Summary
    EudraCT number
    		 2005-003007-36
    Trial protocol
    		 GB  
    Global end of trial date
    31 Aug 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jan 2020
    First version publication date
    22 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HP002A
    Additional study identifiers
    ISRCTN number
    		 ISRCTN18238432
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    South Kensington Campus, London, United Kingdom, SW7 2AZ
    Public contact
    Professor Parviz Habibi, Imperial College London, +44 020 3312 7683, p.habibi@imperial.ac.uk
    Scientific contact
    Professor Parviz Habibi, Imperial College London, +44 020 3312 7683, p.habibi@imperial.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
    29 Aug 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial is to determine the efficacy of helium-oxygen mixtures in the management of bronchiolitis.
    Protection of trial subjects
    None
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Oct 2005
    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
    United Kingdom: 319
    Worldwide total number of subjects
    319
    EEA total number of subjects
    319
    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)
    319
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 361 patients with clinically diagnosed bronchiolitis were considered for eligibility. Consent was obtained for 319 subjects who were randomized and enrolled in the study.

    Pre-assignment
    Screening details
    		 Infants presenting with any respiratory signs or symptoms were screened between the period of 2005 to 2008.

    Period 1
    Period 1 title
    Allocation
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The BREATHE study is the largest phase III, multicenter, double-blinded RCT of Heliox in bronchiolitis. It attempted to resolve the challenges of blinding. The use of special hosing material, identical in appearance for Heliox and Airox ensured that there was no difference in sound generation that could have alerted the investigator to identify the study gas.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Heliox
    Arm description
    		 Participants received treatment with Heliox gas
    Arm type
    		 Experimental

    Investigational medicinal product name
    Heliox21
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gas and solvent for dispersion for injection/infusion
    Routes of administration
    Inhalation use
    Dosage and administration details
    The intervention with additional oxygen titrated via Y-connection tubing, resulting in gas mixes with additional oxygen. Gas delivery was by a tight-fitting 3-valve, nonrebreathing facemask (FM; 1192; Intersurgical) or a nasal cannula (NC; BC 2745-20; Fisher & Paykel Healthcare) if the subject was FM intolerant. Gas drove the continuous positive airway pressure (CPAP) device (EME infant flow driver; CareFusion).

    Arm title
    		 AirOX
    Arm description
    		 Participants received a mixture of 21% oxygen + 79% nitrogen.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Medical Air
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gas and solvent for dispersion for injection/infusion
    Routes of administration
    Inhalation use
    Dosage and administration details
    Treatment is a mixture of 21% oxygen + 79% nitrogen. The intervention with additional oxygen titrated via Y-connection tubing, resulting in gas mixes with additional oxygen. Gas delivery was by a tight-fitting 3-valve, nonrebreathing facemask (FM; 1192; Intersurgical) or a nasal cannula (NC; BC 2745-20; Fisher & Paykel Healthcare) if the subject was FM intolerant. Gas drove the continuous positive airway pressure (CPAP) device (EME infant flow driver; CareFusion).

    Number of subjects in period 1
    		Heliox AirOX
    Started
    160
    159
    Completed
    140
    141
    Not completed
    20
    18
         Consent withdrawn by subject
    3
    6
         Physician decision
    1
    -
         screening failure
    4
    8
         therapy prematurely disrupted
    8
    -
         Protocol deviation
    4
    4
    Period 2
    Period 2 title
    Follow up
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Heliox
    Arm description
    		 Participants received treatment with Heliox gas
    Arm type
    		 Experimental

    Investigational medicinal product name
    Heliox21
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gas and solvent for dispersion for injection/infusion
    Routes of administration
    Inhalation use
    Dosage and administration details
    The intervention with additional oxygen titrated via Y-connection tubing, resulting in gas mixes with additional oxygen. Gas delivery was by a tight-fitting 3-valve, nonrebreathing facemask (FM; 1192; Intersurgical) or a nasal cannula (NC; BC 2745-20; Fisher & Paykel Healthcare) if the subject was FM intolerant. Gas drove the continuous positive airway pressure (CPAP) device (EME infant flow driver; CareFusion).

    Arm title
    		 AirOX
    Arm description
    		 Participants received a mixture of 21% oxygen + 79% nitrogen.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Medical Air
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gas and solvent for dispersion for injection/infusion
    Routes of administration
    Inhalation use
    Dosage and administration details
    Treatment is a mixture of 21% oxygen + 79% nitrogen. The intervention with additional oxygen titrated via Y-connection tubing, resulting in gas mixes with additional oxygen. Gas delivery was by a tight-fitting 3-valve, nonrebreathing facemask (FM; 1192; Intersurgical) or a nasal cannula (NC; BC 2745-20; Fisher & Paykel Healthcare) if the subject was FM intolerant. Gas drove the continuous positive airway pressure (CPAP) device (EME infant flow driver; CareFusion).

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline characteristic provided only for participants that completed the study.
    Number of subjects in period 2 [2]
    		Heliox AirOX
    Started
    140
    141
    Completed
    140
    141
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristic provided only for participants that completed the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Heliox
    Reporting group description
    		 Participants received treatment with Heliox gas

    Reporting group title
    AirOX
    Reporting group description
    		 Participants received a mixture of 21% oxygen + 79% nitrogen.

    Reporting group values
    		 Heliox AirOX Total
    Number of subjects
    		 140 141 281
    Age categorical
    Units: Subjects
        Infants
    		 140 141 281
    Age continuous
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    		 39 (38 to 40) 40 (38 to 40) -
    Gender categorical
    Units: Subjects
        Female
    		 86 85 171
        Male
    		 54 56 110
    Weight at presentation
    Units: kilogram(s)
        median (inter-quartile range (Q1-Q3))
    		 5.65 (4.34 to 7.70) 5.7 (4.4 to 7.7) -
    Modified Wood`s Clinical Asthma Score
    Maximum score 11.
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 3 (2 to 3) 3 (2 to 4) -

    End points

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    End points reporting groups
    Reporting group title
    Heliox
    Reporting group description
    		 Participants received treatment with Heliox gas

    Reporting group title
    AirOX
    Reporting group description
    		 Participants received a mixture of 21% oxygen + 79% nitrogen.
    Reporting group title
    Heliox
    Reporting group description
    		 Participants received treatment with Heliox gas

    Reporting group title
    AirOX
    Reporting group description
    		 Participants received a mixture of 21% oxygen + 79% nitrogen.

    Primary: Total length of treatment (LoT)

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    End point title
    		 Total length of treatment (LoT)
    End point description
    End point type
    Primary
    End point timeframe
    1 week
    End point values
    		 Heliox AirOX
    Number of subjects analysed
    140
    141
    Units: days
        median (inter-quartile range (Q1-Q3))
    1.9 (1.08 to 3.17)
    1.87 (1.11 to 3.34)
    Statistical analysis title
    		 LoT
    Comparison groups
    Heliox v AirOX
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Total length of treatment (LoT) for facemask tolerant participants

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    End point title
    		 Total length of treatment (LoT) for facemask tolerant participants
    End point description
    Heliox - 44 participants, Aieox - 40 participants were facemask tolerant, used a nasal cannula
    End point type
    Primary
    End point timeframe
    1 week
    End point values
    		 Heliox AirOX
    Number of subjects analysed
    44
    40
    Units: day
        median (inter-quartile range (Q1-Q3))
    1.46 (0.85 to 1.95)
    2.01 (0.93 to 2.86)
    Statistical analysis title
    		 LoT with facemask tolerant
    Statistical analysis description
    Heliox - 44 participants, Aieox - 40 participants were facemask tolerant, used nasal cannula
    Comparison groups
    Heliox v AirOX
    Number of subjects included in analysis
    84
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Proportion of cases progressing to CPAP (continuous positive airway pressure)

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    End point title
    		 Proportion of cases progressing to CPAP (continuous positive airway pressure)
    End point description
    End point type
    Secondary
    End point timeframe
    1 week
    End point values
    		 Heliox AirOX
    Number of subjects analysed
    140
    141
    Units: percent
    17
    19
    Statistical analysis title
    		 CPAP
    Comparison groups
    Heliox v AirOX
    Number of subjects included in analysis
    281
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.6

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    1 week
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    5
    Reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: It was no reported any non-serious adverse event.
    Serious adverse events
    		 Overall trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 319 (1.88%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Intubation
         subjects affected / exposed
    6 / 319 (1.88%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 319 (0.00%)

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/23509160
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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