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    Clinical Trial Results:
    The pulmonary effect of bronchodilation on adult VSD patients with persistent or surgically corrected VSD

    Summary
    EudraCT number
    		 2015-005507-89
    Trial protocol
    		 DK  
    Global end of trial date
    11 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Feb 2021
    First version publication date
    26 Feb 2021
    Other versions
    Summary report(s)
    		 Articles from trial

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    191190
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02914652
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Danish Data Protection Agency : 1-16-02-315-16, Danish Medicines Agency: 2016061269, Committee on Biomedical Research Ethics of the Cen: 1-10-72-153-16
    Sponsors
    Sponsor organisation name
    Department of Cardio-Thoracic and Vascular Surgery, Aarhus University Hospital
    Sponsor organisation address
    Palle Juul-Jensens Blvd. 99, Aarhus, Denmark, 8200
    Public contact
    Department of Cardio-Thoracic and V, Aarhus University Hospital, 0045 7845 3080, breiner@ki.au.dk
    Scientific contact
    Department of Cardio-Thoracic and V, Aarhus University Hospital, 0045 31135103, vhjortdal@clin.au.dk
    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
    11 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall purpose of this study is to test whether β2-agonists will affect the cardiopulmonary exercise capacity of VSD-operated patients compared with un-operated VSD-patients and healthy age- and gender-matched controls
    Protection of trial subjects
    All tests where non-invasive and afflicted no pain. Trained medical personal was present at all testing, and the well being of participants was always prioritized. All subjects were assigned a randomization number. The identification list was kept securely locked at our research department, only used in case of Severe Events. In case of severe events at testing or unhealthy findings during data analysis, participants were immediately contacted and referred to the correct hospital department for reevaluation by a specialist and treatment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 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
    Denmark: 96
    Worldwide total number of subjects
    96
    EEA total number of subjects
    96
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    96
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients fulfilling inclusion criteria were previously found in the hospitals medical database. All received an invitation letter with written information and a reply letter. Acceptance followed a oral information visit before inclusion in trial. Healthy volunteers submitted by government official webpage and received the same information.

    Pre-assignment
    Screening details
    		 Patient Journal verifying surgical corrected VSD within 1990 and 1998 at Aarhus University Hospital (152 found, 30 accepted) or unrepaired isolated VSD born between 1985 and 1998 at Aarhus University Hospital (88 found, 30 accepted). Healthy control with no medical record of heart or lung disease (36 included).

    Pre-assignment period milestones
    Number of subjects started
    		 96
    Number of subjects completed
    		 96

    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
    Blinding implementation details
    All inhalers were identical after the Trial Pharmacists remade them. The pharmacists handled packaging and randomization. Therefore no subjects, monitor or investigators knew what inhaler was used at each visit. During data analysis, the test results were labelled A and B, provided by the Trial Pharmacists after data collection, allowing data analysis without knowledge of medicin or placebo until all data analysis was completed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Operated VSD patients
    Arm description
    		 Trial group 1: Surgically corrected for isolated VSD between 1990 and 1998 at Aarhus University Hospital. Receives Ventoline 900 microgram or Placebo in randomized order at first and second visit. Data is the effect of the medication.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ventoline
    Investigational medicinal product code
    PR1
    Other name
    Salbutamol Sulfate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    One dose of 8 puffs and another dose of 1 puff with Ventoline 0,1mg/dosis inhaler. - 9 puffs x 0,1 mg/dosis = 0,9mg before intervention testing.

    Arm title
    		 Unoperated VSD patients
    Arm description
    		 Trial group 2: Diagnosed with isolated VSD born between 1985 and 1998 without surgical or percutaneous closure. - Verified by Echocardiography within the last 4 years. If it is more than 4 it will be verified by our doctors as a systolic murmur or echocardiography. Ventoline 900 microgram or Placebo in randomized order at first and second visit. Data is the effect of the medication.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ventoline
    Investigational medicinal product code
    PR1
    Other name
    Salbutamol Sulfate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    One dose of 8 puffs and another dose of 1 puff with Ventoline 0,1mg/dosis inhaler. - 9 puffs x 0,1 mg/dosis = 0,9mg before intervention testing.

    Arm title
    		 Control group
    Arm description
    		 Control Group: 18-40 years, with no known medical records of heart and lung disease. Ventoline 900 microgram or Placebo in randomized order at first and second visit. Data is the effect of the medication.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ventoline
    Investigational medicinal product code
    PR1
    Other name
    Salbutamol Sulfate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    One dose of 8 puffs and another dose of 1 puff with Ventoline 0,1mg/dosis inhaler. - 9 puffs x 0,1 mg/dosis = 0,9mg before intervention testing.

    Number of subjects in period 1
    		Operated VSD patients Unoperated VSD patients Control group
    Started
    30
    30
    36
    Completed
    30
    30
    36

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Operated VSD patients
    Reporting group description
    		 Trial group 1: Surgically corrected for isolated VSD between 1990 and 1998 at Aarhus University Hospital. Receives Ventoline 900 microgram or Placebo in randomized order at first and second visit. Data is the effect of the medication.

    Reporting group title
    Unoperated VSD patients
    Reporting group description
    		 Trial group 2: Diagnosed with isolated VSD born between 1985 and 1998 without surgical or percutaneous closure. - Verified by Echocardiography within the last 4 years. If it is more than 4 it will be verified by our doctors as a systolic murmur or echocardiography. Ventoline 900 microgram or Placebo in randomized order at first and second visit. Data is the effect of the medication.

    Reporting group title
    Control group
    Reporting group description
    		 Control Group: 18-40 years, with no known medical records of heart and lung disease. Ventoline 900 microgram or Placebo in randomized order at first and second visit. Data is the effect of the medication.

    Reporting group values
    		 Operated VSD patients Unoperated VSD patients Control group Total
    Number of subjects
    		 30 30 36 96
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
        Adults 18-30 years
    		 30 0 0 30
        Adults 18-40 years
    		 0 30 36 66
    Gender categorical
    Units: Subjects
        Female
    		 17 13 18 48
        Male
    		 13 17 18 48
    Smoking status
    Number of cigarettes per week
    Units: Subjects
        <20
    		 4 5 3 12
        >20
    		 3 1 1 5
        Non-smoker
    		 23 24 32 79
    Weight
    Weight mean in kilograms
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 71 ( 12 ) 75 ( 13 ) 72 ( 12 ) -
    Height
    Height in centimeters
    Units: cm
        arithmetic mean (standard deviation)
    		 174 ( 10 ) 174 ( 9 ) 175 ( 9 ) -
    Fat free mass
    Percent of total mass
    Units: percent volume/volume
        arithmetic mean (standard deviation)
    		 76 ( 9 ) 74 ( 8 ) 78 ( 9 ) -
    Subject analysis sets

    Subject analysis set title
    Healthy controls of Operated VSD patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Only 30 of the 36 healthy controls were matched on age and gender to the operated VSD group.

    Subject analysis set title
    Healthy controls of unoperated VSD patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Only 30 healthy controls were matched on age and gender to the unoperated VSD group.

    Subject analysis sets values
    		 Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects
    30
    30
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    0
    0
        From 65-84 years
    0
    0
        85 years and over
    0
    0
        Adults 18-30 years
    30
    0
        Adults 18-40 years
    0
    30
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    15
    13
        Male
    15
    17
    Smoking status
    Number of cigarettes per week
    Units: Subjects
        <20
    3
    3
        >20
    1
    1
        Non-smoker
    26
    26
    Weight
    Weight mean in kilograms
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    72 ( 12 )
    72 ( 12 )
    Height
    Height in centimeters
    Units: cm
        arithmetic mean (standard deviation)
    175 ( 8 )
    176 ( 9 )
    Fat free mass
    Percent of total mass
    Units: percent volume/volume
        arithmetic mean (standard deviation)
    78 ( 10 )
    79 ( 7 )

    End points

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    End points reporting groups
    Reporting group title
    Operated VSD patients
    Reporting group description
    		 Trial group 1: Surgically corrected for isolated VSD between 1990 and 1998 at Aarhus University Hospital. Receives Ventoline 900 microgram or Placebo in randomized order at first and second visit. Data is the effect of the medication.

    Reporting group title
    Unoperated VSD patients
    Reporting group description
    		 Trial group 2: Diagnosed with isolated VSD born between 1985 and 1998 without surgical or percutaneous closure. - Verified by Echocardiography within the last 4 years. If it is more than 4 it will be verified by our doctors as a systolic murmur or echocardiography. Ventoline 900 microgram or Placebo in randomized order at first and second visit. Data is the effect of the medication.

    Reporting group title
    Control group
    Reporting group description
    		 Control Group: 18-40 years, with no known medical records of heart and lung disease. Ventoline 900 microgram or Placebo in randomized order at first and second visit. Data is the effect of the medication.

    Subject analysis set title
    Healthy controls of Operated VSD patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Only 30 of the 36 healthy controls were matched on age and gender to the operated VSD group.

    Subject analysis set title
    Healthy controls of unoperated VSD patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Only 30 healthy controls were matched on age and gender to the unoperated VSD group.

    Primary: Peak minute ventilation response

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    End point title
    		 Peak minute ventilation response [1]
    End point description
    The value is described as the percentual difference between placebo and salbutamol peak minute ventilation. The difference was then afterwards compared between the operated VSD group vs. their healthy controls and unoperated VSD group vs. their healthy controls to see if there was a significant gain.
    End point type
    Primary
    End point timeframe
    Intervention
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    30
    30
    30 [2]
    30 [3]
    Units: % placebo - intervention difference
        arithmetic mean (standard deviation)
    1.72 ( 20.93 )
    2.93 ( 22.56 )
    -4.5 ( 16.5 )
    -2.9 ( 16.3 )
    Notes
    [2] - Matched healthy controls of unoperated VSD patients
    [3] - Matched healthy controls of unoperated VSD patients
    Statistical analysis title
    		 Operated VSD group vs. healthy control group
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Uoperated VSD group vs. healthy control group
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.26
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Peak exercise oxygen uptake

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    End point title
    		 Peak exercise oxygen uptake [4]
    End point description
    The percentual difference of peak oxygen uptake (ml O2 kg^-1 min^-1) from placebo to intervention. Later statistical analysis is between the Operated VSD group vs. their control group and the Unoperated VSD group vs. their control group.
    End point type
    Primary
    End point timeframe
    Over trial
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [5]
    30
    30 [6]
    30 [7]
    Units: % placebo - intervention difference
        arithmetic mean (standard deviation)
    -0.41 ( 2.78 )
    0.09 ( 3.05 )
    0.33 ( 2.89 )
    0.02 ( 2.75 )
    Notes
    [5] - 1 exclusion due to severe congenital scoliosis.
    [6] - Healthy controls matched to the operated VSD group.
    [7] - Healhy controls matched to the unoperated VSD group.
    Statistical analysis title
    		 Operated VSD vs. healthy control group
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unoperated VSD vs. healthy control group
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.92
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Lung clearance index - LCI 2,5

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    End point title
    		 Lung clearance index - LCI 2,5 [8]
    End point description
    The cumulative expired volume at the point where end-tidal inert gas concentration falls below 1/40th of the original concentration, divided by the functional residual capacity (FRC)
    End point type
    Secondary
    End point timeframe
    No intervention
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [9]
    30
    30
    30
    Units: Percent of expected
        arithmetic mean (standard deviation)
    102 ( 21 )
    95 ( 6 )
    97 ( 9 )
    96 ( 7 )
    Notes
    [9] - One patient discarded at data analysis due to severe congenital scoliosis, Outlier.
    Statistical analysis title
    		 Operated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.266
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unoperated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Lung clearance index - Scon

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    End point title
    		 Lung clearance index - Scon [10]
    End point description
    Lung clearance index but focused on the conductive airways.
    End point type
    Secondary
    End point timeframe
    First inclusion
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [11]
    30
    30
    30
    Units: % of expected
        arithmetic mean (standard deviation)
    69 ( 53 )
    86 ( 50 )
    62 ( 46 )
    64 ( 46 )
    Notes
    [11] - 1 patient excluded at before data analysis due to severe congenital scoliosis. Outlier.
    Statistical analysis title
    		 Operated VSD vs. matches healthy controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.582
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unoperated VSD vs. matches healthy controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.089
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Lung clearance index - Sacin

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    End point title
    		 Lung clearance index - Sacin [12]
    End point description
    Lung clearance index but focused on the accinar airways.
    End point type
    Secondary
    End point timeframe
    First inclusion
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [13]
    30
    30
    30
    Units: % of expected
        arithmetic mean (standard deviation)
    100 ( 85 )
    122 ( 118 )
    92 ( 43 )
    96 ( 50 )
    Notes
    [13] - 1 patient excluded due to severe congenital scoliosis
    Statistical analysis title
    		 Operated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.633
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unoperated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.272
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Total Lung Capacity

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    End point title
    		 Total Lung Capacity [14]
    End point description
    Static and dynamic spirometry measurements was performed on IntraMedic Jaeger MasterScreen PFTpro Diffusion System and a BodyBox from CareFusion (IntraMedic, Gentofte, Denmark). Pulmonary function tests were performed by trained and experienced personnel in accordance with current guidelines from the European Respiratory Society.
    End point type
    Secondary
    End point timeframe
    First visit
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [15]
    30
    30
    30
    Units: % of expected
        arithmetic mean (standard deviation)
    101 ( 12 )
    103 ( 11 )
    107 ( 13 )
    105 ( 12 )
    Notes
    [15] - 1 patient excluded due to severe congenital scoliosis
    Statistical analysis title
    		 Operated VSD vs healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.079
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unoperated VSD vs healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.491
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Residual volume

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    End point title
    		 Residual volume [16]
    End point description
    Static and dynamic spirometry measurements was performed on an IntraMedic Jaeger MasterScreen PFTpro Diffusion System and a BodyBox from CareFusion (IntraMedic, Gentofte, Denmark). Pulmonary function tests were performed by trained and experienced personnel in accordance with current guidelines from the European Respiratory Society.
    End point type
    Secondary
    End point timeframe
    First period
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [17]
    30
    30
    30
    Units: % of expected
        arithmetic mean (standard deviation)
    101 ( 21 )
    98 ( 18 )
    94 ( 25 )
    93 ( 24 )
    Notes
    [17] - 1 patient excluded due to severe congenital scoliosis
    Statistical analysis title
    		 Operated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.266
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unoperated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Functional Resiual volume

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    End point title
    		 Functional Resiual volume [18]
    End point description
    Static and dynamic spirometry measurements was performed on an IntraMedic Jaeger MasterScreen PFTpro Diffusion System and a BodyBox from CareFusion (IntraMedic, Gentofte, Denmark). Pulmonary function tests were performed by trained and experienced personnel in accordance with current guidelines from the European Respiratory Society.
    End point type
    Secondary
    End point timeframe
    First period
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [19]
    30
    30
    30
    Units: % of expected
        arithmetic mean (standard deviation)
    124 ( 19 )
    127 ( 21 )
    136 ( 18 )
    133 ( 18 )
    Notes
    [19] - 1 patient excluded due to severe congenital scoliosis
    Statistical analysis title
    		 Operated vs healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.016
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Uoperated vs healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Specific airway resistance

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    End point title
    		 Specific airway resistance [20]
    End point description
    Static and dynamic spirometry measurements was performed on an IntraMedic Jaeger MasterScreen PFTpro Diffusion System and a BodyBox from CareFusion (IntraMedic, Gentofte, Denmark). Pulmonary function tests were performed by trained and experienced personnel in accordance with current guidelines from the European Respiratory Society.
    End point type
    Secondary
    End point timeframe
    First period
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [21]
    30
    30
    30
    Units: % of expected
        arithmetic mean (standard deviation)
    70 ( 26 )
    62 ( 23 )
    65 ( 21 )
    60 ( 21 )
    Notes
    [21] - 1 patient excluded due to severe congenital scoliosis
    Statistical analysis title
    		 Operated vs. matched healthy controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.421
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unoperated vs. matched healthy controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.744
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Forced expiratory volume in 1 second

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    End point title
    		 Forced expiratory volume in 1 second [22]
    End point description
    Static and dynamic spirometry measurements was performed on an IntraMedic Jaeger MasterScreen PFTpro Diffusion System and a BodyBox from CareFusion (IntraMedic, Gentofte, Denmark). Pulmonary function tests were performed by trained and experienced personnel in accordance with current guidelines from the European Respiratory Society.
    End point type
    Secondary
    End point timeframe
    First period
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [23]
    30
    30
    30
    Units: % of expected
        arithmetic mean (standard deviation)
    99 ( 13 )
    104 ( 11 )
    111 ( 13 )
    110 ( 14 )
    Notes
    [23] - 1 patient excluded due to severe congenital scoliosis
    Statistical analysis title
    		 Operated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unoperated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.069
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Forced vital capacity

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    End point title
    		 Forced vital capacity [24]
    End point description
    Static and dynamic spirometry measurements was performed on an IntraMedic Jaeger MasterScreen PFTpro Diffusion System and a BodyBox from CareFusion (IntraMedic, Gentofte, Denmark). Pulmonary function tests were performed by trained and experienced personnel in accordance with current guidelines from the European Respiratory Society.
    End point type
    Secondary
    End point timeframe
    First period
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [25]
    30
    30
    30
    Units: % of expected
        arithmetic mean (standard deviation)
    106 ( 12 )
    111 ( 11 )
    118 ( 13 )
    116 ( 13 )
    Notes
    [25] - 1 patient excluded due to severe congenital scoliosis
    Statistical analysis title
    		 Operated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unoperated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.099
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: FEV1/FVC ratio

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    End point title
    		 FEV1/FVC ratio [26]
    End point description
    Static and dynamic spirometry measurements was performed on an IntraMedic Jaeger MasterScreen PFTpro Diffusion System and a BodyBox from CareFusion (IntraMedic, Gentofte, Denmark). Pulmonary function tests were performed by trained and experienced personnel in accordance with current guidelines from the European Respiratory Society.
    End point type
    Secondary
    End point timeframe
    First period
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [27]
    30
    30
    30
    Units: FEV1/FVC ratio
        arithmetic mean (standard deviation)
    0.8 ( 0.1 )
    0.8 ( 0.07 )
    0.8 ( 0.01 )
    0.81 ( 0.05 )
    Notes
    [27] - 1 patient excluded due to severe congenital scoliosis
    Statistical analysis title
    		 Operated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.627
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unoperated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Diffusion Lung Capacity of Carbonmonoxide

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    End point title
    		 Diffusion Lung Capacity of Carbonmonoxide [28]
    End point description
    For diffusion capacity for carbon monoxide measurements, an IntraMedic Jaeger MasterScreen PFTpro Diffusion System from CareFusion (IntraMedic, Gentofte, Denmark) with software LabManager Version 4.67.0.1 (CareFusion Germany GmbH, Hoechberg, Germany) was used. The single-breath technique was used, with a gas composition of 0.3% carbon monoxide, 10% helium and 21% oxygen, balanced with nitrogen. Tests were performed by trained and experienced personnel in accordance with current guidelines from the European Respiratory Society.
    End point type
    Secondary
    End point timeframe
    First Period
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [29]
    30
    30
    30
    Units: % of expected
        arithmetic mean (standard deviation)
    85 ( 10 )
    92 ( 13 )
    92 ( 12 )
    91 ( 13 )
    Notes
    [29] - 1 patient excluded due to severe congenital scoliosis
    Statistical analysis title
    		 Operated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.042
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Copy of Operated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.742
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Alveolar volume of DLCO

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    End point title
    		 Alveolar volume of DLCO [30]
    End point description
    For diffusion capacity for carbon monoxide measurements, an IntraMedic Jaeger MasterScreen PFTpro Diffusion System from CareFusion (IntraMedic, Gentofte, Denmark) with software LabManager Version 4.67.0.1 (CareFusion Germany GmbH, Hoechberg, Germany) was used. The single-breath technique was used, with a gas composition of 0.3% carbon monoxide, 10% helium and 21% oxygen, balanced with nitrogen. Tests were performed by trained and experienced personnel in accordance with current guidelines from the European Respiratory Society.
    End point type
    Secondary
    End point timeframe
    First period
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [31]
    30
    30
    30
    Units: % of expected
        arithmetic mean (standard deviation)
    92 ( 10 )
    95 ( 11 )
    101 ( 11 )
    100 ( 10 )
    Notes
    [31] - 1 patient excluded due to severe congenital scoliosis
    Statistical analysis title
    		 Operated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unoperated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.085
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Impulse oscillometry - R5

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    End point title
    		 Impulse oscillometry - R5 [32]
    End point description
    R5 is a description of the total conductive airway resistance. A Carefusion Vyntus Impulse Oscillometer using SentrySuite Software and Vyntus Spirometer (IntraMedic, Gentofte, Denmark) with LabManager Version 4.67.0.1 (CareFusion Germany GmbH, Hoechberg, Germany) were used for impulse oscillometry examination. Pulmonary function tests were performed by trained and experienced personnel in accordance with current guidelines from the European Respiratory Society.
    End point type
    Secondary
    End point timeframe
    First period
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [33]
    30
    30
    30
    Units: % of expected
        arithmetic mean (standard deviation)
    125 ( 40 )
    112 ( 26 )
    105 ( 28 )
    101 ( 22 )
    Notes
    [33] - 1 patient excluded due to severe congenital scoliosis
    Statistical analysis title
    		 Operated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.027
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unoperated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.079
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Impulse oscillometry - R20

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    End point title
    		 Impulse oscillometry - R20 [34]
    End point description
    R20 is a description of the upper airway resistance of the conductive airway system. A Carefusion Vyntus Impulse Oscillometer using SentrySuite Software and Vyntus Spirometer (IntraMedic, Gentofte, Denmark) with LabManager Version 4.67.0.1 (CareFusion Germany GmbH, Hoechberg, Germany) were used for impulse oscillometry examination. Pulmonary function tests were performed by trained and experienced personnel in accordance with current guidelines from the European Respiratory Society.
    End point type
    Secondary
    End point timeframe
    First period
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [35]
    30
    30
    30
    Units: % of expected
        arithmetic mean (standard deviation)
    124 ( 31 )
    122 ( 28 )
    113 ( 26 )
    109 ( 22 )
    Notes
    [35] - 1 patient excluded due to severe congenital scoliosis
    Statistical analysis title
    		 Operated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.127
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unoperated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.124
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Impulse oscillometry - Diff 5-20

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    End point title
    		 Impulse oscillometry - Diff 5-20 [36]
    End point description
    Diff R5-R20 is a description of how much the lower airways attributes the total airway resistance of the conductive airway system A Carefusion Vyntus Impulse Oscillometer using SentrySuite Software and Vyntus Spirometer (IntraMedic, Gentofte, Denmark) with LabManager Version 4.67.0.1 (CareFusion Germany GmbH, Hoechberg, Germany) were used for impulse oscillometry examination. Pulmonary function tests were performed by trained and experienced personnel in accordance with current guidelines from the European Respiratory Society.
    End point type
    Secondary
    End point timeframe
    First period
    Notes
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The total group of healthy controls included was used to provide two groups of healthy controls that was matched with age and gender for the operated VSD group and the unoperated VSD group. Hence 30 in each group for the analysis. We did not perform analysis on the total group of healthy controls.
    End point values
    		 Operated VSD patients Unoperated VSD patients Healthy controls of Operated VSD patients Healthy controls of unoperated VSD patients
    Number of subjects analysed
    29 [37]
    30
    30
    30
    Units: % of resistance in small airways
        arithmetic mean (standard deviation)
    22 ( 20 )
    16 ( 17 )
    14 ( 14 )
    13 ( 13 )
    Notes
    [37] - 1 patient excluded due to severe congenital scoliosis
    Statistical analysis title
    		 Operated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Operated VSD patients v Healthy controls of Operated VSD patients
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.076
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unoperated VSD vs. healthy matched controls
    Statistical analysis description
    Differences between groups were assessed using paired or unpaired students t-tests or two-way analyses of variance (ANOVA), as appropriate, for continuous data.
    Comparison groups
    Unoperated VSD patients v Healthy controls of unoperated VSD patients
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.558
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Minimum heart rate over 24h Holter

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    End point title
    		 Minimum heart rate over 24h Holter
    End point description
    End point type
    Secondary
    End point timeframe
    24h holter monitoration after placebo.
    End point values
    		 Operated VSD patients Unoperated VSD patients Control group
    Number of subjects analysed
    30
    30
    36
    Units: beats per minute
        arithmetic mean (standard deviation)
    49 ( 8 )
    51 ( 7 )
    50 ( 9 )
    Statistical analysis title
    		 Anova between groups
    Comparison groups
    Operated VSD patients v Unoperated VSD patients v Control group
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.879
    Method
    		 ANOVA
    Confidence interval

    Secondary: Mean heart rate over 24h Holter

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    End point title
    		 Mean heart rate over 24h Holter
    End point description
    End point type
    Secondary
    End point timeframe
    24h holter monitoration after placebo visit.
    End point values
    		 Operated VSD patients Unoperated VSD patients Control group
    Number of subjects analysed
    30
    30
    36
    Units: beats per minute
        arithmetic mean (standard deviation)
    72 ( 8 )
    75 ( 10 )
    73 ( 9 )
    Statistical analysis title
    		 Anova between groups
    Comparison groups
    Operated VSD patients v Unoperated VSD patients v Control group
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.555
    Method
    		 ANOVA
    Confidence interval

    Secondary: Maximum heart rate of 24h holter

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    End point title
    		 Maximum heart rate of 24h holter
    End point description
    End point type
    Secondary
    End point timeframe
    24h holter after placebo visit
    End point values
    		 Operated VSD patients Unoperated VSD patients Control group
    Number of subjects analysed
    30
    30
    36
    Units: beats per minute
        arithmetic mean (standard deviation)
    140 ( 23 )
    141 ( 25 )
    150 ( 26 )
    Statistical analysis title
    		 Anova between groups
    Comparison groups
    Unoperated VSD patients v Control group v Operated VSD patients
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.212
    Method
    		 ANOVA
    Confidence interval

    Secondary: Arrhythmias 24h holter

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    End point title
    		 Arrhythmias 24h holter
    End point description
    End point type
    Secondary
    End point timeframe
    24h holter after placebo visit
    End point values
    		 Operated VSD patients Unoperated VSD patients Control group
    Number of subjects analysed
    30
    30
    36
    Units: Number of participants
        >200 Premature Ventricular Contractions
    9
    2
    0
        Supraventricular tachyarrhythmia
    6
    1
    4
        Ventricular tachyarrhythmia
    2
    2
    1
        Sinus pause
    3
    1
    2
        Atrioventricular block
    3
    2
    0
    Statistical analysis title
    		 Premature ventricular contractions
    Statistical analysis description
    Difference in number of participants in each group.
    Comparison groups
    Operated VSD patients v Unoperated VSD patients v Control group
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Supraventricular tachyarrhythmia
    Statistical analysis description
    Difference in number of participants in each group.
    Comparison groups
    Operated VSD patients v Unoperated VSD patients v Control group
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.128
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Ventricular tachyarrhythmia
    Comparison groups
    Operated VSD patients v Unoperated VSD patients v Control group
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.708
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Sinus pause
    Statistical analysis description
    Difference in number of participants in each group.
    Comparison groups
    Operated VSD patients v Unoperated VSD patients v Control group
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.553
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Anova of Atrioventricular block
    Comparison groups
    Operated VSD patients v Unoperated VSD patients v Control group
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.174
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Mean RR interval

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    End point title
    		 Mean RR interval
    End point description
    End point type
    Secondary
    End point timeframe
    24h holter after placebo visit
    End point values
    		 Operated VSD patients Unoperated VSD patients Control group
    Number of subjects analysed
    30
    30
    36
    Units: milliseconds
        arithmetic mean (standard deviation)
    816 ( 93 )
    803 ( 100 )
    805 ( 85 )
    Statistical analysis title
    		 Anova between groups
    Comparison groups
    Operated VSD patients v Control group v Unoperated VSD patients
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.857
    Method
    		 ANOVA
    Confidence interval

    Secondary: Root mean square of the successive normal sinus interval difference

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    End point title
    		 Root mean square of the successive normal sinus interval difference
    End point description
    End point type
    Secondary
    End point timeframe
    24h holter after placebo visit
    End point values
    		 Operated VSD patients Unoperated VSD patients Control group
    Number of subjects analysed
    30
    30
    36
    Units: Number of participants
    13
    5
    4
    Statistical analysis title
    		 Difference between groups
    Comparison groups
    Operated VSD patients v Unoperated VSD patients v Control group
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Study participant inclusion went between June 2016 to December 2017, extended from Juli 2017 due participants response had longer waiting time than anticipated.
    Adverse event reporting additional description
    We experienced no severe adverse events during the trial and all adverse events was reported per protocol.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Operated VSD patients
    Reporting group description
    		 Trial group 1: Surgically corrected for isolated VSD between 1990 and 1998 at Aarhus University Hospital. Receives Ventoline 900 microgram or Placebo in randomized order at first and second visit. Data is the effect of the medication.

    Reporting group title
    Unoperated VSD patients
    Reporting group description
    		 Trial group 2: Diagnosed with isolated VSD born between 1985 and 1998 without surgical or percutaneous closure. - Verified by Echocardiography within the last 4 years. If it is more than 4 it will be verified by our doctors as a systolic murmur or echocardiography. Ventoline 900 microgram or Placebo in randomized order at first and second visit. Data is the effect of the medication.

    Reporting group title
    Control group
    Reporting group description
    		 Control Group: 18-40 years, with no known medical records of heart and lung disease. Ventoline 900 microgram or Placebo in randomized order at first and second visit. Data is the effect of the medication.

    Serious adverse events
    		 Operated VSD patients Unoperated VSD patients Control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Operated VSD patients Unoperated VSD patients Control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 30 (20.00%)
    4 / 30 (13.33%)
    2 / 36 (5.56%)
    Investigations
    Fatigue
    Additional description: After VO2 max testing some participants reported fatigue in the following days after testing. This is a commonly known muscle soreness from max testing if the participant is not an athlete.
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    1
    Vascular disorders
    Vasovagal presyncope
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    Cardiac disorders
    AV block
    Additional description: One participant had 2 events of 2nd degree AV block during Holter monitoration. It was discussed with the trial cardiologist who analyzed the data as benign without need of further investigation or precaution.
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    Ventricular tachycardia
    Additional description: 1 participant was diagnosed with ventricular tachycardia during the holter monitoration. Participant was unaffected and otherwise healthy with no previous history of cardiac arrhythmia. Trial cardiologist took patient in for further treatment.
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Headache
    Additional description: One participant had headache during fatigue period after the physical activity testing of one visit. Was wall afterwards.
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    Social circumstances
    Minor car accident
    Additional description: One participant was in a minor car accident on its way to the second visit. Was physically assessed and had no physical or psycological issue and wanted to participate in the second visit, which was allowed.
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Exercise induced asthma
    Additional description: One healthy participant experienced exercise induced asthma symptoms after the placebo testing, but not during the exercise testing. This participant was advised to further diagnostics and treatment with its own physician.
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Palpations left arm
    Additional description: 1 Participant had palpations in left arm extremity during physical exercise testing with placebo. No issue with Salbutamol. Also participant reported known issue in the musculoskeletal system when exercising and no ECG changes during testing.
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    common cold
    Additional description: 1 participant had the common cold during the second visit, but was well and not with nasal congestion.
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Dec 2016
    We had to extend the trial inclusion time due to poor response from invited participants. Therefore the study participant inclusion ended December 2017 instead of Juli 2017.

    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/30001944
    http://www.ncbi.nlm.nih.gov/pubmed/30454724
    http://www.ncbi.nlm.nih.gov/pubmed/32147225
    http://www.ncbi.nlm.nih.gov/pubmed/30233808
    For support, Contact us.
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