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    Clinical Trial Results:
    HELIOX-DRIVEN BETA2-AGONISTS NEBULIZATION FOR CHILDREN WITH MODERATE TO SEVERE ACUTE ASTHMA: A RANDOMIZED CONTROLLED TRIAL

    Summary
    EudraCT number
    		 2015-004959-50
    Trial protocol
    		 ES  
    Global end of trial date
    18 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Mar 2022
    First version publication date
    13 Mar 2022
    Other versions
    Summary report(s)
    		 Synopsis Heliox AP

    Trial information

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    Trial identification
    Sponsor protocol code
    Heliox-AP
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    S.E. Carburos Metálicos S.A. grupo Air Products
    Sponsor organisation address
    C/Qunitanavides 17 Edificio 3, Madrid, Spain, 28050
    Public contact
    European Regulatory Affairs Manager, S.E. Carburos Metálicos S.A. grupo Air Products, 0034 606935762, hoischv@airproducts.com
    Scientific contact
    European Regulatory Affairs Manager, S.E. Carburos Metálicos S.A. grupo Air Products, 0034 606935762, hoischv@airproducts.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
    18 Nov 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Nov 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of heliox (He/O2 = 78%/22%) versus Synthetic Medicinal Air (O2 22%/N2 78%) for intermittent nebulization of fast-acting beta-agonists bronchodilators (salbutamol) in children and adolescents with acute moderate to severe asthma in a pediatric ED.
    Protection of trial subjects
    The study protocol and all its amendments, and the patient information sheet(s) were reviewed and approved by the appropriate independent ethics committee.
    Background therapy
    		 Irrespective of the group to which the trial patients were randomized, they received regular treatment for this type of patients with salbutamol and oral corticosteroids
    Evidence for comparator
    		 The comparator has the National Marketing Authorization for hypoxia prevention since January 28th 2010
    Actual start date of recruitment
    12 Sep 2016
    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: 54
    Worldwide total number of subjects
    54
    EEA total number of subjects
    54
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    46
    Adolescents (12-17 years)
    8
    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
    		 Informed consent was obtained from the legal guardian of the study participants before initiation of therapy in the ED (at allocation). The details of the study were explained to the parents/guardians/child allowing them time to think and ask questions. A copy of the informed consent was given to the parents/guardians/child.

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 54
    Number of subjects completed
    		 54

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    Although the cylinders containing the gases (Synthetic Medicinal Air and heliox) were identical and the patients were blind to the assigned treatment group, the double-blind procedure was not possible in this specific case, because the use of heliox causes typical changes in the patients’ voices (“Donald Duck voice”)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 First Arm
    Arm description
    		 Three successive treatments (every 30 min.) of salbutamol (5 mg/30 min.) nebulized with heliox (He/O2 = 78%/22%).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Heliox
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    Patients received 3 successive treatments (every 30 min.) of salbutamol (5 mg/30 min.) nebulized with heliox (He/O2 = 78%/22%) as a carrier gas. Each treatment was applied until the nebulizer was dry, followed by a 5 to 10-minute wash-out period. Heliox was administered from the nebulizer via a non-rebreather mask at room temperature

    Arm title
    		 Second Arm
    Arm description
    		 Three successive treatments (every 30 min.) of salbutamol (5 mg/30 min.) nebulized with Synthetic Medicinal Air.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Synthetic Medicinal Air
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    Patients received three successive treatments (every 30 min.) of salbutamol (5 mg/30 min.) nebulized with Synthetic Medicinal Air as a carrier gas. Each treatment was applied until the nebulizer was dry, followed by a 5 to 10-minute wash-out period. Synthetic Medicinal Air was administered from the nebulizer via a non-rebreather mask at room temperature.

    Number of subjects in period 1
    		First Arm Second Arm
    Started
    27
    27
    Completed
    26
    27
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    First Arm
    Reporting group description
    		 Three successive treatments (every 30 min.) of salbutamol (5 mg/30 min.) nebulized with heliox (He/O2 = 78%/22%).

    Reporting group title
    Second Arm
    Reporting group description
    		 Three successive treatments (every 30 min.) of salbutamol (5 mg/30 min.) nebulized with Synthetic Medicinal Air.

    Reporting group values
    		 First Arm Second Arm Total
    Number of subjects
    		 27 27 54
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 24 22 46
        Adolescents (12-17 years)
    		 3 5 8
    Gender categorical
    Units: Subjects
        Female
    		 9 8 17
        Male
    		 18 19 37
    Hospitlizations in previous years
    Units: Subjects
        yes
    		 2 4 6
        no
    		 25 23 48
    Maintenance treatment
    Units: Subjects
        yes
    		 10 7 17
        no
    		 17 20 37
    Use of corticosteroids in the previous 24 hours
    Units: Subjects
        yes
    		 5 3 8
        no
    		 22 24 46
    Use of B2 agonists in the previous 24 hours
    Units: Subjects
        yes
    		 25 23 48
        no
    		 2 4 6
    Weight
    Units: Kilograms
        arithmetic mean (standard deviation)
    		 32.9 ( 15.1 ) 32.1 ( 9.4 ) -
    Height
    Units: centimeters
        arithmetic mean (standard deviation)
    		 133.7 ( 18.5 ) 134.1 ( 14.5 ) -
    Duration of attack before ED presentation
    Units: hours
        arithmetic mean (standard deviation)
    		 31.2 ( 35.1 ) 30.2 ( 35.1 ) -
    Asthma duration in years
    Units: years
        arithmetic mean (standard deviation)
    		 5.4 ( 3.0 ) 5.9 ( 2.9 ) -
    Heart rate
    Units: bpm
        arithmetic mean (standard deviation)
    		 108.9 ( 16.8 ) 109.0 ( 21.7 ) -
    Oxygen saturation
    Units: percentage
        arithmetic mean (standard deviation)
    		 94.9 ( 2.4 ) 94.8 ( 1.8 ) -
    Pulmonary score
    Units: 0-9
        arithmetic mean (standard deviation)
    		 5.0 ( 1.0 ) 4.7 ( 0.8 ) -
    Systolic pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 112.3 ( 10.5 ) 113.7 ( 9.2 ) -
    Diastolic Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 66.3 ( 6.8 ) 67.9 ( 6.9 ) -

    End points

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    End points reporting groups
    Reporting group title
    First Arm
    Reporting group description
    		 Three successive treatments (every 30 min.) of salbutamol (5 mg/30 min.) nebulized with heliox (He/O2 = 78%/22%).

    Reporting group title
    Second Arm
    Reporting group description
    		 Three successive treatments (every 30 min.) of salbutamol (5 mg/30 min.) nebulized with Synthetic Medicinal Air.

    Primary: Mean change Pulmonary Score from baseline at 30 minutes

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    End point title
    		 Mean change Pulmonary Score from baseline at 30 minutes
    End point description
    The pulmonary score (PS) is a clinical score system based on respiratory rate, wheezing and the use of accessory respiratory muscles, which has been validated as a measure of the severity of asthma exacerbation in children and adolescents. The highest possible score is 9 and a PS of >3 is defined as moderate or severe disease. Pulmonary score (PS) was measure in all patients at the start of the treatment and then every 30 minutes until it ends (90 min).
    End point type
    Primary
    End point timeframe
    Measured in all of the patients at the start of treatment and at 30 minutes
    End point values
    		 First Arm Second Arm
    Number of subjects analysed
    27
    27
    Units: Pulmonary score units
        arithmetic mean (standard deviation)
    -1.7 ( 1.1 )
    -1.1 ( 0.8 )
    Attachments
    		 Pulmonary score variation
    Statistical analysis title
    		 Primary Efficacy Analysis (Mean change PS)
    Comparison groups
    First Arm v Second Arm
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Primary: Mean change in Pulmonary Score from Baseline at 60 minutes

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    End point title
    		 Mean change in Pulmonary Score from Baseline at 60 minutes
    End point description
    The pulmonary score (PS) is a clinical score system based on respiratory rate, wheezing and the use of accessory respiratory muscles, which has been validated as a measure of the severity of asthma exacerbation in children and adolescents. The highest possible score is 9 and a PS of >3 is defined as moderate or severe disease. Pulmonary score (PS) was measure in all patients at the start of the treatment and then every 30 minutes until it ends (90 min).
    End point type
    Primary
    End point timeframe
    Measured in all of the patients at the start of treatment and at 60 minutes
    End point values
    		 First Arm Second Arm
    Number of subjects analysed
    25
    27
    Units: Pulmonary score units
        arithmetic mean (standard deviation)
    -2.8 ( 1.2 )
    -2.0 ( 1.2 )
    Attachments
    		 Pulmonary score variation
    Statistical analysis title
    		 Primary Efficacy Analysis (Mean change PS)
    Comparison groups
    First Arm v Second Arm
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Primary: Mean change in Pulmonary Score from Baseline at 90 minutes

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    End point title
    		 Mean change in Pulmonary Score from Baseline at 90 minutes
    End point description
    The pulmonary score (PS) is a clinical score system based on respiratory rate, wheezing and the use of accessory respiratory muscles, which has been validated as a measure of the severity of asthma exacerbation in children and adolescents. The highest possible score is 9 and a PS of >3 is defined as moderate or severe disease. Pulmonary score (PS) was measure in all patients at the start of the treatment and then every 30 minutes until it ends (90 min).
    End point type
    Primary
    End point timeframe
    Measured in all of the patients at the start of treatment and at 90 minutes
    End point values
    		 First Arm Second Arm
    Number of subjects analysed
    23
    26
    Units: Pulmonary Score units
        arithmetic mean (standard deviation)
    -3.6 ( 1.2 )
    -2.7 ( 1.3 )
    Attachments
    		 Pulmonary score variation
    Statistical analysis title
    		 Primary Efficacy Analysis (Mean change PS)
    Comparison groups
    First Arm v Second Arm
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Percentage of patients who require hospitalization at the end of treatment (PS ≥ 3)

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    End point title
    		 Percentage of patients who require hospitalization at the end of treatment (PS ≥ 3)
    End point description
    End point type
    Secondary
    End point timeframe
    Patients that presented with PS ≥ 3 at the end of the treatment
    End point values
    		 First Arm Second Arm
    Number of subjects analysed
    26
    27
    Units: patients
    3
    4
    Statistical analysis title
    		 Percentage of patients who require hospitalization
    Statistical analysis description
    A percentage comparison of hospitalized patients
    Comparison groups
    First Arm v Second Arm
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Percentage of patients who require Intensive care unit admission throughout the study

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    End point title
    		 Percentage of patients who require Intensive care unit admission throughout the study
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout the study
    End point values
    		 First Arm Second Arm
    Number of subjects analysed
    27
    27
    Units: patients
    0
    0
    Statistical analysis title
    		 Percentage of patients who require ICU admission
    Comparison groups
    First Arm v Second Arm
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Percentage of patients who require orotracheal intubation throughout the study

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    End point title
    		 Percentage of patients who require orotracheal intubation throughout the study
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout the study
    End point values
    		 First Arm Second Arm
    Number of subjects analysed
    27
    27
    Units: patients
    0
    0
    Statistical analysis title
    		 Percentage of patients who require intubation
    Comparison groups
    First Arm v Second Arm
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Percentage of patients who died throughout the study

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    End point title
    		 Percentage of patients who died throughout the study
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout the study
    End point values
    		 First Arm Second Arm
    Number of subjects analysed
    27
    27
    Units: patients
    0
    0
    Statistical analysis title
    		 Percentage of patients who died during study
    Comparison groups
    First Arm v Second Arm
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval

    Other pre-specified: Median survival time of patients discharged due to achievement of PS < 3 throughout the treatment

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    End point title
    		 Median survival time of patients discharged due to achievement of PS < 3 throughout the treatment
    End point description
    Survival analysis performed at 30, 60 and 90 minutes
    End point type
    Other pre-specified
    End point timeframe
    Medians for survival time
    End point values
    		 First Arm Second Arm
    Number of subjects analysed
    27
    27
    Units: minute
        median (confidence interval 95%)
    60 (51.5 to 68.4)
    90 (80.9 to 99.0)
    Attachments
    		 Survival analysis
    Statistical analysis title
    		 Survival analysis of patients with PS<3
    Statistical analysis description
    All patients enrolled in the study were analyzed. In the case of patients who were lost before the end of treatment (90 min.), the LOGRANK test was used, considering patients withdrawn due to an improvement in their pulmonary score.
    Comparison groups
    First Arm v Second Arm
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Logrank
    Parameter type
    		 Chi-square Logrank Mantel-Cox
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events were reported on a regular basis to the sponsor as specified in the protocol
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Heliox
    Reporting group description
    		 -

    Reporting group title
    Synthetic Medicinal Air
    Reporting group description
    		 -

    Serious adverse events
    		 Heliox Synthetic Medicinal Air
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 27 (11.11%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysnea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lack of drug effect
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 27 (11.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Heliox Synthetic Medicinal Air
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 27 (85.19%)
    7 / 27 (25.93%)
    Nervous system disorders
    Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    Somnolence
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Presyncope
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 27 (11.11%)
    2 / 27 (7.41%)
         occurrences all number
    3
    2
    Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Feeling cold
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    0
    3
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
    Additional description: The use of heliox causes typical changes in the patients’ voices (“Donald Duck voice”) that in this case was reported as dysphonia by investigators
    alternative assessment type: Non-systematic
         subjects affected / exposed
    23 / 27 (85.19%)
    0 / 27 (0.00%)
         occurrences all number
    23
    0
    Psychiatric disorders
    Anxiety disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Aug 2018
    The key objetive was to modify age range (from 6-16 to 5-16 years) and modify the asthma diagnosis criteria, updating them according to the international asthma guidelines (2018). Changes in PEF (Peak Flow Meter) were removed as secondary endpoints.

    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
    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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