Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   37700   clinical trials with a EudraCT protocol, of which   6177   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Randomized, Double blind, Placebo controlled, Two-Way Crossover 7-day study to Investigate the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Repeat Dose Inhaled GW642444 25μg in Children aged 5-11 years with Persistent Asthma

    Summary
    EudraCT number
    2012-000741-12
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    12 Apr 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Mar 2016
    First version publication date
    14 May 2015
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    HZA112776
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01453296
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, +1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, +1 866-435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000431-PIP01-08
    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
    27 May 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Apr 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the safety and tolerability following administration of GW642444 25 μg, via a novel dry powder inhaler, once-daily for 7 days in subjects aged 5–11 years.
    Protection of trial subjects
    A parent was required to stay with the subjects for the long days in the clinic. As much as possible children in the same age group were scheduled for visits on the same day. Games and movies were provided for diversion during the long clinic days. Effort was made to have the same staff members work with the children to help reduce anxiety. Topical anesthetics were used at injection site to reduce discomfort from blood collections. An indwelling cannula was inserted for serial blood draws, to prevent the pain and distress associated with repeated needle sticks.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Mar 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 28
    Worldwide total number of subjects
    28
    EEA total number of subjects
    0
    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)
    28
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Participants were enrolled into one of two cohorts based upon age; the younger cohort was enrolled after a review of the safety/pharmacokinetic data of at least six participants from the older cohort. Each participant was assigned to treatment randomly; assignment was not to be influenced by whether participants were in Cohort 1 or Cohort 2.

    Pre-assignment
    Screening details
    A Baseline assessment was carried out on Day 1 of the first treatment period. Participants were then randomized to one of the two possible treatment sequences (Vilanterol [VI] 25 micrograms [µg] followed by matching Placebo; matching placebo followed by VI 25 µg) in a 1:1 ratio in an AB or BA sequence.

    Period 1
    Period 1 title
    Treatment Period 1 (Overall)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sequence 1: VI 25 µg followed by Placebo
    Arm description
    Participants received vilanterol (VI) 25 micrograms (µg) and matching placebo in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Vilanterol; placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    Vilanterol 25mg or Placebo once daily x 14 days; 7 day wash out (w/o); crossover

    Arm title
    Sequence 2: Placebo followed by VI 25 µg
    Arm description
    Participants received placebo and VI 25 µg in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Arm type
    Experimental; placebo

    Investigational medicinal product name
    Vilanterol; placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    Vilanterol 25mg or Placebo once daily x 14 days; 7 day w/o; crossover

    Number of subjects in period 1
    Sequence 1: VI 25 µg followed by Placebo Sequence 2: Placebo followed by VI 25 µg
    Started
    14
    14
    Completed
    13
    13
    Not completed
    1
    1
         Met protocol-Defined Stopping Criteria
    1
    -
         Adverse event, non-fatal
    -
    1
    Period 2
    Period 2 title
    Washout Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sequence 1: VI 25 µg followed by Placebo
    Arm description
    Participants received vilanterol (VI) 25 micrograms (µg) and matching placebo in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Arm type
    Experimental: placebo

    Investigational medicinal product name
    Vilanterol; placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    Vilanterol 25mg or Placebo once daily x 14 days; 7 day w/o; crossover

    Arm title
    Sequence 2: Placebo followed by VI 25 µg
    Arm description
    Participants received placebo and VI 25 µg in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Arm type
    Experimental: placebo

    Investigational medicinal product name
    Vilanterol; placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    Vilanterol 25mg or Placebo once daily x 14 days; 7 day w/o; crossover

    Number of subjects in period 2
    Sequence 1: VI 25 µg followed by Placebo Sequence 2: Placebo followed by VI 25 µg
    Started
    13
    13
    Completed
    13
    13
    Period 3
    Period 3 title
    Treatment Period 2
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sequence 1: VI 25 µg followed by Placebo
    Arm description
    Participants received vilanterol (VI) 25 micrograms (µg) and matching placebo in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Arm type
    Experimental: placebo

    Investigational medicinal product name
    Vilanterol; placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    Vilanterol 25mg or Placebo once daily x 14 days; 7 day w/o; crossover

    Arm title
    Sequence 2: Placebo followed by VI 25 µg
    Arm description
    Participants received placebo and VI 25 µg in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Arm type
    Experimental: placebo

    Investigational medicinal product name
    Vilanterol; placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    Vilanterol 25mg or Placebo once daily x 14 days; 7 day w/o; crossover

    Number of subjects in period 3
    Sequence 1: VI 25 µg followed by Placebo Sequence 2: Placebo followed by VI 25 µg
    Started
    13
    13
    Completed
    11
    13
    Not completed
    2
    0
         Adverse event, non-fatal
    1
    -
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period 1 (Overall)
    Reporting group description
    Participants received either vilanterol (VI) 25 micrograms (µg) or matching placebo in the first of two 14-day treatment periods, followed by a repeat dose of the other therapy (the therapy not received in the first treatment period) in the second 14-day treatment period. Inhaled VI 25 µg or matching placebo was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.

    Reporting group values
    Treatment Period 1 (Overall) Total
    Number of subjects
    28 28
    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)
    28 28
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    0 0
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    8 ± 1.9 -
    Gender categorical
    Units: Subjects
        Female
    10 10
        Male
    18 18
    Race, Customized
    Units: Subjects
        African American/African Heritage
    5 5
        White - White/Caucasian/European Heritage
    22 22
        Mixed Race
    1 1

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Sequence 1: VI 25 µg followed by Placebo
    Reporting group description
    Participants received vilanterol (VI) 25 micrograms (µg) and matching placebo in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.

    Reporting group title
    Sequence 2: Placebo followed by VI 25 µg
    Reporting group description
    Participants received placebo and VI 25 µg in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Reporting group title
    Sequence 1: VI 25 µg followed by Placebo
    Reporting group description
    Participants received vilanterol (VI) 25 micrograms (µg) and matching placebo in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.

    Reporting group title
    Sequence 2: Placebo followed by VI 25 µg
    Reporting group description
    Participants received placebo and VI 25 µg in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.
    Reporting group title
    Sequence 1: VI 25 µg followed by Placebo
    Reporting group description
    Participants received vilanterol (VI) 25 micrograms (µg) and matching placebo in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.

    Reporting group title
    Sequence 2: Placebo followed by VI 25 µg
    Reporting group description
    Participants received placebo and VI 25 µg in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All participants who received matching placebo in one or both of the two 14-day treatment periods. Matching placebo was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.

    Subject analysis set title
    VI 25 µg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All participants who received VI 25 µg in one or both of the 14-day treatment periods. Inhaled VI 25 µg was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.

    Subject analysis set title
    VI 25 µg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All participants who received VI 25 µg in one or both of the 14-day treatment periods. Inhaled VI 25 µg was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.

    Primary: Number of participants with any adverse event (AE) or any serious adverse event (SAE) during the Treatment Period

    Close Top of page
    End point title
    Number of participants with any adverse event (AE) or any serious adverse event (SAE) during the Treatment Period [1]
    End point description
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations. Refer to the General AE/SAE module for a complete list of AEs and SAEs.
    End point type
    Primary
    End point timeframe
    From the start of study medication until Week 11 (Visit 8)/Early Withdrawal
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available.
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [2]
    27 [3]
    Units: Participants
        Any AE
    6
    9
        Any SAE
    0
    0
    Notes
    [2] - All Subjects Population: all participants who received at least one dose of study medication
    [3] - All Subjects Population: all participants who received at least one dose of study medication
    No statistical analyses for this end point

    Primary: Basophil, eosinophil, lymphocyte, monocyte, total neutrophil, platelet, and white blood cell count values at Day 14 of the respective treatment period

    Close Top of page
    End point title
    Basophil, eosinophil, lymphocyte, monocyte, total neutrophil, platelet, and white blood cell count values at Day 14 of the respective treatment period [4]
    End point description
    Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelets, and white blood cell (WBC) count at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 49)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available.
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [5]
    27 [6]
    Units: 10^9 cells per liter (GI/L)
    arithmetic mean (standard deviation)
        Basophils, n=24, 25
    0.021 ± 0.0145
    0.034 ± 0.0185
        Eosinophils, n=24, 25
    0.276 ± 0.3002
    0.348 ± 0.3458
        Lymphocytes, n=24, 25
    2.404 ± 0.8652
    2.419 ± 0.8729
        Monocytes, n=24, 25
    0.268 ± 0.131
    0.376 ± 0.1419
        Total neutrophils, n=24, 25
    3.354 ± 1.3054
    3.127 ± 0.9625
        Platelets, n=23, 25
    280.7 ± 54.11
    279.4 ± 54.71
        WBCs, n=24, 25
    6.32 ± 1.808
    6.3 ± 1.64
    Notes
    [5] - All Subjects Population,Only those participants available at the specified time points were analyzed
    [6] - All Subjects Population,Only those participants available at the specified time points were analyzed
    No statistical analyses for this end point

    Primary: Hemoglobin and mean corpuscle hemoglobin concentration (MCHC) values at Day 14 of the respective treatment period

    Close Top of page
    End point title
    Hemoglobin and mean corpuscle hemoglobin concentration (MCHC) values at Day 14 of the respective treatment period [7]
    End point description
    Blood samples were collected for the measurement of hemoglobin and MCHC at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 49)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available.
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [8]
    27 [9]
    Units: Grams per liter (g/L)
    arithmetic mean (standard deviation)
        Hemoglobin, n=24, 25
    133 ± 11.3
    130.7 ± 11.22
        MCHC, n=24, 25
    337.1 ± 5.5
    338.3 ± 11.6
    Notes
    [8] - All Subjects Population, only those participants available at the specified time points were analyed
    [9] - All Subjects Population, only those participants available at the specified time points were analyed
    No statistical analyses for this end point

    Primary: Reticulocyte and Red Blood Cell (RBC) values at Day 14 of the respective treatment period

    Close Top of page
    End point title
    Reticulocyte and Red Blood Cell (RBC) values at Day 14 of the respective treatment period [10]
    End point description
    Blood samples were collected for the measurement of reticulocytes and RBCs at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 49)
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available.
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [11]
    27 [12]
    Units: 10^12 cells per liter (TI/L)
    arithmetic mean (standard deviation)
        Reticulocytes, n=24, 25
    0.0501 ± 0.020696
    0.05275 ± 0.024571
        RBCs, n=24, 25
    4.6 ± 0.374
    4.47 ± 0.339
    Notes
    [11] - All Subjects Population,only those participants available at the specified time points were analyzed
    [12] - All Subjects Population,only those participants available at the specified time points were analyzed
    No statistical analyses for this end point

    Primary: Hematocrit value at Day 14 of the respective treatment period

    Close Top of page
    End point title
    Hematocrit value at Day 14 of the respective treatment period [13]
    End point description
    Blood samples were collected for the measurement of hematocrit at Day 14 of the respective treatment period. Hematocrit is a measure of the percentage of the volume of the whole blood that is composed of red blood cells, as determined by separation of red blood cells from the plasma (usually by centrifugation). Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 49)
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available.
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    24 [14]
    25 [15]
    Units: proportion of 1
    arithmetic mean (standard deviation)
        proportion of 1
    0.3948 ± 0.0343
    0.3863 ± 0.02617
    Notes
    [14] - All Subjects Population,only those participants available at the specified time points were analyzed
    [15] - All Subjects Population,only those participants available at the specified time points were analyzed
    No statistical analyses for this end point

    Primary: Mean Corpuscle Volume (MCV) value at Day 14 of the respective treatment period

    Close Top of page
    End point title
    Mean Corpuscle Volume (MCV) value at Day 14 of the respective treatment period [16]
    End point description
    Blood samples were collected for the measurement of MCV at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 49)
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available.
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    24 [17]
    25 [18]
    Units: 10^15 femtoliters (fL) per cell
    arithmetic mean (standard deviation)
        10^15 femtoliters (fL) per cell
    86 ± 4.08
    86.6 ± 3.59
    Notes
    [17] - All Subjects Population,only those participants available at the specified time points were analyzed
    [18] - All Subjects Population,only those participants available at the specified time points were analyzed
    No statistical analyses for this end point

    Primary: Mean Corpuscle Hemoglobin (MCH) value at Day 14 of the respective treatment period

    Close Top of page
    End point title
    Mean Corpuscle Hemoglobin (MCH) value at Day 14 of the respective treatment period [19]
    End point description
    Blood samples were collected for the measurement of MCH at Day 14 of the respective treatment period . Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 49)
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available.
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    24 [20]
    25 [21]
    Units: 10^12 picograms (pg) per cell
    arithmetic mean (standard deviation)
        10^12 picograms (pg) per cell
    28.97 ± 1.337
    29.29 ± 1.464
    Notes
    [20] - All Subjects Population,only those participants available at the specified time points were analyzed
    [21] - All Subjects Population,only those participants available at the specified time points were analyzed
    No statistical analyses for this end point

    Primary: Alanine amino transferase (ALT), alkaline phosphatase (ALP), aspartate amino transferase (AST), and gamma glutamyl transferase (GGT) values at Day 14 of the respective treatment period

    Close Top of page
    End point title
    Alanine amino transferase (ALT), alkaline phosphatase (ALP), aspartate amino transferase (AST), and gamma glutamyl transferase (GGT) values at Day 14 of the respective treatment period [22]
    End point description
    Blood samples were collected for the measurement of ALT, ALP, AST, and GGT at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 49)
    Notes
    [22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available.
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [23]
    27 [24]
    Units: International units per liter (IU/L)
    arithmetic mean (standard deviation)
        ALT, n=22, 25
    13.9 ± 4.21
    13.5 ± 3.56
        ALP, n=22, 25
    260.5 ± 109.65
    273.4 ± 103.51
        AST, n=22, 24
    27.7 ± 6.11
    25.5 ± 4.52
        GGT, n=22, 25
    14.1 ± 4.12
    13.6 ± 3.51
    Notes
    [23] - All Subjects Population,only those participants available at the specified time points were analyzed
    [24] - All Subjects Population,only those participants available at the specified time points were analyzed
    No statistical analyses for this end point

    Primary: Albumin and total protein values at Day 14 of the respective treatment period

    Close Top of page
    End point title
    Albumin and total protein values at Day 14 of the respective treatment period [25]
    End point description
    Blood samples were collected for the measurement of albumin and total protein at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 49)
    Notes
    [25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available.
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [26]
    27 [27]
    Units: Grams per liter
    arithmetic mean (standard deviation)
        Albumin, n=22, 25
    42.8 ± 2.95
    43.2 ± 1.96
        Total protein, n=22, 25
    67.9 ± 4.82
    68.6 ± 3.16
    Notes
    [26] - All Subjects Population,only those participants available at the specified time points were analyzed
    [27] - All Subjects Population,only those participants available at the specified time points were analyzed
    No statistical analyses for this end point

    Primary: Calcium, chloride, carbon dioxide (CO2) content/bicarbonate, glucose, potassium, sodium, and urea/blood urea nitrogen (BUN) values at Day 14 of the respective treatment period

    Close Top of page
    End point title
    Calcium, chloride, carbon dioxide (CO2) content/bicarbonate, glucose, potassium, sodium, and urea/blood urea nitrogen (BUN) values at Day 14 of the respective treatment period [28]
    End point description
    Blood samples were collected for the measurement of calcium, chloride, carbon dioxide content/bicarbonate (CO2/BI), glucose, potassium, sodium, and urea/BUN at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 49)
    Notes
    [28] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available.
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [29]
    27 [30]
    Units: Millimoles per liter (mmol/L)
    arithmetic mean (standard deviation)
        Calcium, n=22, 24
    2.327 ± 0.1357
    2.359 ± 0.0666
        Chloride, n=22, 25
    105.5 ± 3.9
    105.1 ± 2.01
        CO2 content/bicarbonate, n=22, 24
    17.6 ± 2.3
    18.1 ± 1.98
        Glucose, n=22, 25
    4.95 ± 0.51
    5.04 ± 0.513
        Potassium, n=22, 24
    4.3 ± 0.408
    4.33 ± 0.242
        Sodium, n=22, 25
    137.7 ± 2.43
    137.8 ± 2.12
        Urea/BUN, n=22, 25
    4.91 ± 1.368
    4.48 ± 1.15
    Notes
    [29] - All Subjects Population,only those participants available at the specified time points were analyzed
    [30] - All Subjects Population,only those participants available at the specified time points were analyzed
    No statistical analyses for this end point

    Primary: Total bilirubin, direct bilirubin, creatinine, and uric acid values at Day 14 of the respective treatment period

    Close Top of page
    End point title
    Total bilirubin, direct bilirubin, creatinine, and uric acid values at Day 14 of the respective treatment period [31]
    End point description
    Blood samples were collected for the measurement of total bilirubin, direct bilirubin, creatinine, and uric acid at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.
    End point type
    Primary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 49)
    Notes
    [31] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available.
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [32]
    27 [33]
    Units: Micromoles per liter (µmol/L)
    arithmetic mean (standard deviation)
        Total bilirubin, n=22, 25
    6.2 ± 2.22
    5.8 ± 1.99
        Direct bilirubin, n=22, 25
    1.7 ± 0.94
    1.2 ± 1
        Creatinine, n=22, 25
    39.45 ± 7.653
    39.35 ± 6.731
        Uric acid, n=22, 25
    241.4 ± 69.51
    245.6 ± 47.27
    Notes
    [32] - All Subjects Population,only those participants available at the specified time points were analyzed
    [33] - All Subjects Population,only those participants available at the specified time points were analyzed
    No statistical analyses for this end point

    Primary: Peak expiratory flow on Day 1, Day 8, and Day 14 of the respective treatment period

    Close Top of page
    End point title
    Peak expiratory flow on Day 1, Day 8, and Day 14 of the respective treatment period [34]
    End point description
    Peak Expiratory Flow (PEF) is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF is calculated as the maximum of three readings taken at each timepoint for each participant. Baseline is defined as the pre-dose measurement at Day 1 for the respective period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).
    End point type
    Primary
    End point timeframe
    Day 1, Day 8, and Day 14 of the respective treatment period (up to Study Day 49)
    Notes
    [34] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available.
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [35]
    28 [36]
    Units: liters/minute
    arithmetic mean (standard deviation)
        Day 1, Baseline, n=26, 28
    230.6 ± 72.55
    233 ± 68.55
        Day 1, 20 minutes post-dose, n=26, 28
    237.5 ± 69.65
    245.6 ± 73.47
        Day 8, Pre-dose, n=26, 28
    232.1 ± 64.76
    228.8 ± 64.42
        Day 8, 20 minutes post-dose, n=25, 28
    233.8 ± 220
    240.7 ± 65.66
        Day 14, Pre-dose, n=24, 26
    240.3 ± 75.9
    239 ± 72.02
        Day 14, 20 minutes post-dose, n=24, 26
    243.3 ± 75.18
    248.1 ± 76.2
    Notes
    [35] - All Subjects Population,only those participants available at the specified time points were analyzed
    [36] - All Subjects Population,only those participants available at the specified time points were analyzed
    No statistical analyses for this end point

    Primary: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Day 1, Day 8, and Day 14 of the respective treatment period

    Close Top of page
    End point title
    Systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Day 1, Day 8, and Day 14 of the respective treatment period [37]
    End point description
    SBP and DBP were measured at Day 1, Day 8, and Day 14 of the respective treatment period. PD=post-dose. Baseline is defined as the pre-dose measurement at Day 1 for the respective period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).
    End point type
    Primary
    End point timeframe
    Day 1, Day 8, and Day 14 of the respective treatment period (up to Study Day 49)
    Notes
    [37] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available.
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [38]
    28 [39]
    Units: Millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        Day 1 SBP, Baseline, n=26, 28
    101.8 ± 6.59
    102.9 ± 9.21
        Day 1 SBP, 10 minutes PD, n=26, 28
    100.7 ± 7.59
    102.4 ± 7.69
        Day 1 SBP, 30 minutes PD, n=26, 28
    100.9 ± 9.35
    103.5 ± 6.89
        Day 1 SBP, 45 minutes PD, n=26, 28
    100.9 ± 7.41
    103.5 ± 7.05
        Day 1 SBP, 74 minutes PD, n=26, 28
    102.7 ± 7.95
    104.4 ± 6.81
        Day 1 SBP, 2 hours PD, n=26, 28
    103.3 ± 8.16
    104.8 ± 7.82
        Day 8 SBP, Pre-dose, n=25, 28
    99.6 ± 6.92
    103.7 ± 8.64
        Day 8 SBP, 30 minutes PD, n=25, 28
    101.7 ± 7.29
    102.9 ± 7.31
        Day 8 SBP, 1 hour PD, n=25, 28
    101.8 ± 8.38
    103.6 ± 7.17
        Day 14 SBP, Pre-dose, n=24, 26
    101.5 ± 9.18
    103.9 ± 6.15
        Day 14 SBP, 10 minutes PD, n=24, 26
    101.3 ± 9.98
    103.7 ± 6.7
        Day 14 SBP, 30 minutes PD, n=24, 26
    103.9 ± 8.72
    102.9 ± 8.91
        Day 14 SBP, 45 minutes PD, n=24, 26
    103.6 ± 7.95
    103.4 ± 7.03
        Day 14 SBP, 75 minues PD, n=24, 26
    104.9 ± 8.33
    103.9 ± 6.36
        Day 14 SBP, 2 hours PD, n=24, 26
    103 ± 6.68
    102.9 ± 6.42
        Day 14 SBP, 4 hours PD, n=24, 26
    102.2 ± 7.8
    106 ± 5.2
        Day 14 SBP, 8 hours PD, n=24, 26
    104.7 ± 8.92
    104.7 ± 7.76
        Day 1 DBP, Baseline, n=26, 28
    62 ± 5.12
    62.1 ± 6.38
        Day 1 DBP, 10 minutes PD, n=26, 28
    62.4 ± 7.16
    63.5 ± 4.08
        Day 1 DBP, 30 minutes PD, n=26, 28
    62.4 ± 6.55
    62.6 ± 4.29
        Day 1 DBP, 45 minutes PD, n=26, 28
    63 ± 7.93
    63.3 ± 5.99
        Day 1 DBP, 75 minutes PD, n=26, 28
    63.3 ± 5.74
    64.4 ± 7.91
        Day 1 DBP, 2 hours PD, n=26, 28
    63 ± 4.81
    63.4 ± 5.49
        Day 8 DBP, Pre-dose, n=25, 28
    63.7 ± 8.17
    62.8 ± 5.58
        Day 8 DBP, 30 minutes PD, n=25, 28
    62.3 ± 9.19
    62.4 ± 7.26
        Day 8 DBP, 1 hour PD, n=25, 28
    63.2 ± 6.68
    62.2 ± 7.9
        Day 14 DBP, Pre-dose, n=24, 26
    60.8 ± 5.7
    63.8 ± 8.14
        Day 14 DBP, 10 minutes PD, n=24, 26
    60.9 ± 6.55
    62.7 ± 7.07
        Day 14 DBP, 30 minutes PD, n=24, 26
    62.8 ± 3.83
    63.7 ± 7.88
        Day 14 DBP, 45 minutes PD, n=24, 26
    61.9 ± 4.05
    64.5 ± 4.68
        Day 14 DBP, 75 minutes PD, n=23, 26
    63 ± 5.12
    63.6 ± 6.34
        Day 14 DBP, 2 hours PD, n=23, 26
    64.1 ± 7.33
    63.3 ± 5.5
        Day 14 DBP, 4 hours PD, n=23, 26
    62.3 ± 8.56
    63.9 ± 6.59
        Day 14 DBP, 8 hours PD, n=23, 26
    63.2 ± 4.78
    63.3 ± 7.29
    Notes
    [38] - All Subjects Population,only those participants available at the specified time points were analyzed
    [39] - All Subjects Population,only those participants available at the specified time points were analyzed
    No statistical analyses for this end point

    Primary: Maximum heart rate at Day 1 and Day 14 of the respective treatment period

    Close Top of page
    End point title
    Maximum heart rate at Day 1 and Day 14 of the respective treatment period
    End point description
    Heart rate (HR) was measured at Day 1 and Day 14 of the respective treatment period. hr=hour. For 0-8 hr parameters, treatment, period, participant Baseline, and period Baseline were fitted as fixed effects, and participant was fitted as a random effect. For 0-2 hr parameters, treatment, period, day (1 and 14), participant Baseline, period Baseline, and treatment*day interaction were fitted as fixed effects, and participant was fitted as a random effect. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).
    End point type
    Primary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [40]
    28 [41]
    Units: Beats per minute
    least squares mean (standard error)
        Day 1 maximum HR (0-2 hr), n=26, 28
    83.6 ± 1.44
    86.1 ± 1.4
        Day 14 maximum HR (0-2 hr), n=24, 26
    84.3 ± 1.38
    85 ± 1.35
        Day 14 maximum HR (0-8 hr), n=24, 26
    88.1 ± 1.45
    88.6 ± 1.41
    Notes
    [40] - All Subjects Population,only those participants available at the specified time points were analyzed
    [41] - All Subjects Population,only those participants available at the specified time points were analyzed
    Statistical analysis title
    Analysis 1
    Comparison groups
    Placebo v VI 25 µg
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [42]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    5.7
    Notes
    [42] - Estimation based analysis. Day 1 maximum HR (0-2 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo.
    Statistical analysis title
    Analysis 2
    Comparison groups
    Placebo v VI 25 µg
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [43]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.4
         upper limit
    3.7
    Notes
    [43] - Estimation based analysis. Day 14 maximum HR (0-2 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo.
    Statistical analysis title
    Analysis 3
    Comparison groups
    Placebo v VI 25 µg
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [44]
    Method
    Parameter type
    Median difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.6
         upper limit
    3.6
    Notes
    [44] - Estimation based analysis. Day 14 maximum HR (0-8 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo.

    Primary: Weighted mean heart rate at Day 1 and Day 14 of the respective treatment period

    Close Top of page
    End point title
    Weighted mean heart rate at Day 1 and Day 14 of the respective treatment period
    End point description
    Heart rate (HR) was measured at Day 1 and Day 14 of the respective treatment period. hr=hour. Weighted means were derived using the linear trapezoidal rule. Actual relative times were used for the calculation except where actual times were missing. If any actual times were missing, planned relative times were used for these observations. For 0-8 hr parameters, treatment, period, participant Baseline, and period Baseline were fitted as fixed effects, and participant was fitted as a random effect. For 0-2 hr parameters, treatment, period, day (1 and 14), participant Baseline, period Baseline, and treatment*day interaction were fitted as fixed effects, and participant was fitted as a random effect. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).
    End point type
    Primary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [45]
    28 [46]
    Units: Beats per minute
    least squares mean (standard error)
        Day 1 weighted HR (0-2 hr), n=26, 28
    76.39 ± 1.311
    79.2 ± 1.285
        Day 14 weighted mean HR (0-2 hr), n=23, 26
    76.11 ± 1.309
    77.67 ± 1.264
        Day 14 weighted mean HR (0-8 hr), n=23, 26
    80.54 ± 1.458
    80.65 ± 1.404
    Notes
    [45] - All Subjects Population,only those participants available at the specified time points were analyzed
    [46] - All Subjects Population,only those participants available at the specified time points were analyzed
    Statistical analysis title
    Analysis 1
    Comparison groups
    Placebo v VI 25 µg
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [47]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    5.7
    Notes
    [47] - Estimation based analysis. Day 1 weighted HR (0-2 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo.
    Statistical analysis title
    Analysis 2
    Comparison groups
    Placebo v VI 25 µg
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [48]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.4
         upper limit
    3.7
    Notes
    [48] - Estimation based analysis. Day 14 weighted HR (0-2 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo.
    Statistical analysis title
    Analysis 3
    Comparison groups
    Placebo v VI 25 µg
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [49]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.6
         upper limit
    3.6
    Notes
    [49] - Estimation based analysis. Day 14 weighted HR (0-8 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo.

    Primary: Maximum QTcF at Day 1 and Day 14 of the respective treatment period

    Close Top of page
    End point title
    Maximum QTcF at Day 1 and Day 14 of the respective treatment period
    End point description
    The electrocardiographic (ECG) parameter QT duration corrected using Fridericia’s formula (QTcF) was measured at Day 1 and Day 14 of the respective treatment period. hr=hour. For 0-8 hr parameters, treatment, period, participant Baseline, and period Baseline were fitted as fixed effects, and participant was fitted as a random effect. For 0-2 hr parameters, treatment, period, day (1 and 14), participant Baseline, period Baseline, and treatment*day interaction were fitted as fixed effects, and participant was fitted as a random effect. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).
    End point type
    Primary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [50]
    28 [51]
    Units: milliseconds
    least squares mean (standard error)
        Day 1 maximum QTcF (0-2 hr), n=26, 28
    405.6 ± 2.29
    406.6 ± 2.22
        Day 14 maximum QTcF (0-2 hr), n=24, 26
    406.1 ± 2.06
    407.7 ± 2
        Day 14 maximum QTcF (0-8 hr), n=24, 26
    407.8 ± 1.87
    409.2 ± 1.82
    Notes
    [50] - All Subjects Population,only those participants available at the specified time points were analyzed
    [51] - All Subjects Population,only those participants available at the specified time points were analyzed
    Statistical analysis title
    Analysis 1
    Comparison groups
    Placebo v VI 25 µg
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [52]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.5
         upper limit
    6.6
    Notes
    [52] - Estimation based analysis. Day 1 maximum QTcF (0-2 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo.
    Statistical analysis title
    Analysis 2
    Comparison groups
    Placebo v VI 25 µg
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [53]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.2
         upper limit
    6.3
    Notes
    [53] - Estimation based analysis. Day 14 maximum QTcF (0-2 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo.
    Statistical analysis title
    Analysis 3
    Comparison groups
    Placebo v VI 25 µg
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [54]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3
         upper limit
    5.7
    Notes
    [54] - Estimation based analysis. Day 14 maximum QTcF (0-8 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo.

    Primary: Weighted mean QTcF at Day 1 and Day 14 of the respective treatment period

    Close Top of page
    End point title
    Weighted mean QTcF at Day 1 and Day 14 of the respective treatment period
    End point description
    The electrocardiographic (ECG) parameter QT duration corrected using Fridericia’s formula (QTcF) was measured at Day 1 and Day 14 of the respective treatment period. hr=hour. Actual relative times were used for the calculation except where actual times were missing. If any actual times were missing, planned relative times were used for these observations. For 0-8 hr parameters, treatment, period, participant Baseline, and period Baseline were fitted as fixed effects, and participant was fitted as a random effect. For 0-2 hr parameters, treatment, period, day (1 and 14), participant Baseline, period Baseline, and treatment*day interaction were fitted as fixed effects, and participant was fitted as a random effect. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).
    End point type
    Primary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [55]
    28 [56]
    Units: milliseconds
    least squares mean (standard error)
        Day 1 weighted mean QTcF (0-2 hr), n=26, 28
    394.21 ± 2.007
    396.22 ± 1.96
        Day 14 weighted mean QTcF (0-2 hr), n=23, 26
    395.09 ± 2.122
    398.03 ± 2.024
        Day 14 weighted mean QTcF (0-8 hr), n=23, 26
    393.43 ± 1.867
    396.62 ± 1.793
    Notes
    [55] - All Subjects Population,only those participants available at the specified time points were analyzed
    [56] - All Subjects Population,only those participants available at the specified time points were analyzed
    Statistical analysis title
    Analysis 1
    Comparison groups
    Placebo v VI 25 µg
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [57]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    2.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.59
         upper limit
    6.61
    Notes
    [57] - Estimation based analysis. Day 1 weighted QTcF (0-2 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo.
    Statistical analysis title
    Analysis 2
    Comparison groups
    Placebo v VI 25 µg
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [58]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    2.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.93
         upper limit
    7.81
    Notes
    [58] - Estimation based analysis. Day 14 weighted QTcF (0-2 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo.
    Statistical analysis title
    Analysis 3
    Comparison groups
    Placebo v VI 25 µg
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [59]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    3.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    7.08
    Notes
    [59] - Estimation based analysis. Day 14 weighted QTcF (0-8 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo.

    Secondary: AUC(0-t) and AUC(0-8) on Day 14 of the respective treatment period

    Close Top of page
    End point title
    AUC(0-t) and AUC(0-8) on Day 14 of the respective treatment period
    End point description
    Area under the concentration-time (AUC) curve from time zero (pre-dose) to the last time AUC(0-t) and from time zero to 8 hours AUC(0-8) of quantifiable concentration of VI on Day 14 of the respective treatment period was measured. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, 4, 6, and 8 hours post-dose for participants who were >=20 kilograms and pre-dose; 10 min and 30 min post-dose; and 1, 2, and 4 hours post-dose for participants who were <=20 kilograms on Day 14 of the respective treatment period. Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Pharmacokinetic Population. Pharmacokinetic (PK) Population: all participants in the All Subjects Population for whom a PK sample was obtained and analyzee. Only those participants available at the specified time points were analyzed (represented by n=X,X in the category titles).
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    VI 25 µg
    Number of subjects analysed
    25 [60]
    Units: picograms*hour per milliliter (pg*hr/mL)
    geometric mean (confidence interval 95%)
        AUC(0-t), n=0,25
    132.8 (96 to 183.8)
        AUC(0-8), n=0,19
    181.7 (145 to 227.7)
    Notes
    [60] - PK Population:all participants in All Subjects Population for whom a PK sample was obtained/analyzed
    No statistical analyses for this end point

    Secondary: Cmax on Day 14 of the respective treatment period

    Close Top of page
    End point title
    Cmax on Day 14 of the respective treatment period
    End point description
    Cmax is defined as the maximum observed concentration on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, 4, 6, and 8 hours post-dose for participants who were >=20 kilograms and pre-dose; 10 min and 30 min post-dose; and 1, 2, and 4 hours post-dose for participants who were <=20 kilograms on Day 14 of the respective treatment period.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    VI 25 µg
    Number of subjects analysed
    25 [61]
    Units: picograms per milliliter (pg/mL)
        geometric mean (confidence interval 95%)
    97.44 (64.83 to 146.45)
    Notes
    [61] - PK Population
    No statistical analyses for this end point

    Secondary: tmax, t1/2, and t at Day 14 of the respective treatment period

    Close Top of page
    End point title
    tmax, t1/2, and t at Day 14 of the respective treatment period
    End point description
    tmax is defined as the time to reach the observed maximum concentration, t1/2 is defined as the time required to reduce the plasma concentration to one half its initial value, and t is defined as the time of the last observed quantifiable concentration on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, 4, 6, and 8 hours post-dose for participants who were >=20 kilograms and pre-dose; 10 min and 30 min post-dose; and 1, 2, and 4 hours post-dose for participants who were <=20 kilograms on Day 14 of the respective treatment period. PK Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the PK Population.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    VI 25 µg
    Number of subjects analysed
    25 [62]
    Units: hours
    median (full range (min-max))
        tmax, n=23
    0.2 (0 to 1)
        t1/2, n=14
    3.131 (1.06 to 6.32)
        t, n=23
    6 (1 to 8.13)
    Notes
    [62] - PK Population. Only those participants available at the specified time points were analyzed (n=X).
    No statistical analyses for this end point

    Secondary: Blood glucose and potassium on Day 14 of the respective treatment period

    Close Top of page
    End point title
    Blood glucose and potassium on Day 14 of the respective treatment period
    End point description
    Blood glucose and potassium values were measured on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, 4, 6, and 8 hours post-dose for participants who were >=20 kilograms and pre-dose; 10 min and 30 min post-dose; and 1, 2, and 4 hours post-dose for participants who were <=20 kilograms on Day 14 of the respective treatment period. Weighted means were derived using the linear trapezoidal rule. Actual relative times were used for the calculation except where actual times were missing. If any actual times were missing, planned relative times were used for these observations. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg. Treatment and period were fitted as fixed effects and participant was fitted as a random effect.
    End point type
    Secondary
    End point timeframe
    Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [63]
    27 [64]
    Units: Millimoles per liter (mmol/L)
    least squares mean (standard error)
        Maximum Glucose (0-2 hr), n=24, 26
    5.55 ± 0.184
    5.57 ± 0.182
        Maximum Glucose (0-8 hr), n=24, 26
    6.22 ± 0.187
    6.03 ± 0.183
        Weighted Mean Glucose (0-2 hr), n=21, 25
    5.02 ± 0.114
    5.06 ± 0.109
        Weighted Mean Glucose (0-8 hr), n=19, 24
    5.26 ± 0.108
    5.21 ± 0.1
        Minimum Potassium (0-2 hr), n=23, 26
    4.05 ± 0.04
    4 ± 0.038
        Minimum Potassium (0-8 hr), n=24, 26
    3.89 ± 0.06
    3.87 ± 0.059
        Weighted Mean Potassium (0-2 hr), n=19, 22
    4.21 ± 0.049
    4.23 ± 0.046
        Weighted Mean Potassium (0-8 hr), n=17, 22
    4.05 ± 0.052
    4.11 ± 0.049
    Notes
    [63] - All Subjects Population,only those participants available at the specified time points were analyzed
    [64] - All Subjects Population,only those participants available at the specified time points were analyzed
    No statistical analyses for this end point

    Secondary: Average oropharyngeal cross-sectional area on Day 1 and Day 14 of the respective treatment period

    Close Top of page
    End point title
    Average oropharyngeal cross-sectional area on Day 1 and Day 14 of the respective treatment period
    End point description
    During the pharyngometry assessment, participants inhaled through a wavetube, which had a mouthpiece with the same dimensions as the mouthpiece on the dry powder inhaler used for the study. This technique was used to measure the size of the throat and mouth (oropharynx) in the form of pharyngograms. Pharyngometry data were recorded for each day (Day 1 and Day 14 of the respective treatment period) using the mean of four measurements (pharyngograms), and the average oropharyngeal cross-sectional area was calculated. All Subjects Population. Only those participants available at the specified time point were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the All Subjects Population.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [65]
    27 [66]
    Units: centimeters squared (cm^2)
    arithmetic mean (standard deviation)
        Day 1, n=15, 13
    5.65 ± 1.834
    4.42 ± 2.31
        Day 14, n=14, 15
    5.47 ± 1.661
    5.16 ± 2.139
    Notes
    [65] - All Subjects Population. Only those participants available at the specified time point were analyzed
    [66] - All Subjects Population. Only those participants available at the specified time point were analyzed
    No statistical analyses for this end point

    Secondary: Distance of assessment on Day 1 and Day 14 of the respective treatment period

    Close Top of page
    End point title
    Distance of assessment on Day 1 and Day 14 of the respective treatment period
    End point description
    During the pharyngometry assessment, participants inhaled through a wavetube, which had a mouthpiece with the same dimensions as the mouthpiece on the dry powder inhaler used for this study. This technique was used to measure the size of the throat and mouth (oropharynx) in the form of pharyngograms. Distance of assessment is defined as the distance (length measured in centimeters [cm]) estimated to be from the lips to the larynx. Pharyngometry data were recorded for each day (Days 1 and 14 of the respective treatment period) using the mean of four measurements (pharyngograms), and the average oropharyngeal cross-sectional area was calculated. All Subjects Population. Only those participants available at the specified time point were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the All Subjects Population.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [67]
    27 [68]
    Units: centimeters (cm)
    arithmetic mean (standard deviation)
        Day 1, n=15, 13
    18.4 ± 1.502
    18.26 ± 1.824
        Day 14, n=14, 15
    18.46 ± 1.395
    18.41 ± 1.276
    Notes
    [67] - All Subjects Population. Only those participants available at the specified time point were analyzed
    [68] - All Subjects Population. Only those participants available at the specified time point were analyzed
    No statistical analyses for this end point

    Secondary: Oropharyngeal volume on Day 1 and Day 14 of the respective treatment period

    Close Top of page
    End point title
    Oropharyngeal volume on Day 1 and Day 14 of the respective treatment period
    End point description
    During the pharyngometry assessment, participants inhaled through a wavetube, which had a mouthpiece with the same dimensions as the mouthpiece on the dry powder inhaler used for this study. This technique was used to measure the size of the throat and mouth (oropharynx) in the form of pharyngograms. Oropharyngeal volume is defined as the volume (centimeters cubed [cm^3]) of the mouth and throat estimated to be from the lips to the larynx. Pharyngometry data were recorded for each day (Days 1 and 14 of the respective treatment period) using the mean of four measurements (pharyngograms), and the average oropharyngeal cross-sectional area was calculated. All Subjects Population. Only those participants available at the specified time point were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the All Subjects Population.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [69]
    27 [70]
    Units: cm^3
    arithmetic mean (standard deviation)
        Day 1, n=15, 13
    102.33 ± 32.451
    78.6 ± 39.296
        Day 14, n=14, 15
    102.26 ± 36.322
    93.35 ± 37.19
    Notes
    [69] - All Subjects Population. Only those participants available at the specified time point were analyzed
    [70] - All Subjects Population. Only those participants available at the specified time point were analyzed
    No statistical analyses for this end point

    Secondary: Average flow rate and Peak Inspiratory Flow Rate (PIFR) on Day 1 and Day 14 of the respective treatment period

    Close Top of page
    End point title
    Average flow rate and Peak Inspiratory Flow Rate (PIFR) on Day 1 and Day 14 of the respective treatment period
    End point description
    During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Average flow rate is defined as the average inspiratory flow rate (Liters [L]/min) across the inhalation profile when inhaling across the resistance of the inhaler. PIFR is defined as the Peak Inspiratory Flow Rate (L/min) of the inhalation profile when inhaling across the resistance of the inhaler.The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was used for each day (Days 1 and 14 of the respective treatment period), and the average flow rate and PIFR were determined. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [71]
    27 [72]
    Units: Liters per minute (L/min)
    arithmetic mean (standard deviation)
        Day 1, Average flow rate, n=23, 25
    38.84 ± 9.44
    42.23 ± 10.952
        Day 14, Average flow rate, n=23, 25
    40.45 ± 10.538
    42.08 ± 10.191
        Day 1, PIFR, n=23, 25
    58.27 ± 14.258
    61.41 ± 16.513
        Day 14, PIFR, n=23, 25
    60.93 ± 14.901
    61.79 ± 15.348
    Notes
    [71] - All Subjects Population. Only those participants available at the specified time point were analyzed
    [72] - All Subjects Population. Only those participants available at the specified time point were analyzed
    No statistical analyses for this end point

    Secondary: Inhalation time on Day 1 and Day 14 of the respective treatment period

    Close Top of page
    End point title
    Inhalation time on Day 1 and Day 14 of the respective treatment period
    End point description
    During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Inhalation time is defined as the duration of the inhalation(s) when inhaling across the resistance of the inhaler. The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was used for each day (Days 1 and 14 of the respective treatment period), and the inhalation time was determined. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [73]
    27 [74]
    Units: Seconds (sec)
    arithmetic mean (standard deviation)
        Day 1, n=23, 25
    1.45 ± 0.604
    1.36 ± 0.551
        Day 14, n=23, 25
    1.35 ± 0.528
    1.34 ± 0.476
    Notes
    [73] - All Subjects Population. Only those participants available at the specified time point were analyzed
    [74] - All Subjects Population. Only those participants available at the specified time point were analyzed
    No statistical analyses for this end point

    Secondary: Inhaled volume on Day 1 and Day 14 of the respective treatment period

    Close Top of page
    End point title
    Inhaled volume on Day 1 and Day 14 of the respective treatment period
    End point description
    During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Inhaled volume is defined as the volume of air (Liters) inhaled during the inhalation across the resistance of the inhaler. The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was used for each day (Days 1 and 14 of the respective treatment period), and the inhalaled volume was determined. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [75]
    27 [76]
    Units: Liters
    arithmetic mean (standard deviation)
        Day 1, n=23, 25
    0.93 ± 0.433
    0.92 ± 0.343
        Day 14, n=23, 25
    0.9 ± 0.426
    0.95 ± 0.417
    Notes
    [75] - All Subjects Population. Only those participants available at the specified time point were analyzed
    [76] - All Subjects Population. Only those participants available at the specified time point were analyzed
    No statistical analyses for this end point

    Secondary: Peak pressure drop on Day 1 and Day 14 of the respective treatment period

    Close Top of page
    End point title
    Peak pressure drop on Day 1 and Day 14 of the respective treatment period
    End point description
    During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Peak pressure drop is defined as the maximum pressure drop (kilopascal [kPa]) achieved during inhalation across the resistance of the inhaler. The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was calculated for each day (Days 1 and 14 of the respective treatment period), and used for subsequent modeling and prediction of dose emission attributes. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    Placebo VI 25 µg
    Number of subjects analysed
    26 [77]
    27 [78]
    Units: Kilopascal (kpa)
    arithmetic mean (standard deviation)
        Day 1, n=23, 25
    2.97 ± 1.275
    3.33 ± 1.632
        Day 14, n=23, 25
    3.23 ± 1.479
    3.33 ± 1.35
    Notes
    [77] - All Subjects Population. Only those participants available at the specified time point were analyzed
    [78] - All Subjects Population. Only those participants available at the specified time point were analyzed
    No statistical analyses for this end point

    Secondary: Total emitted dose (TED) on Day 1 and Day 14 of the respective treatment period

    Close Top of page
    End point title
    Total emitted dose (TED) on Day 1 and Day 14 of the respective treatment period
    End point description
    The total emitted dose (TED) is defined as the mass (micrograms) of the nominal dose that passes beyond the throat. The recorded inhalation profiles of the participants and the mouth-throat (oropharyngeal) models of the sizes that approximated to pharyngometry measurements of the participants were used in conjunction with the electronic Lung (eLung) for in vitro assessment. The eLung is a breathing simulator that replicates the selected inhalation profile with an active inhaler placed at the lips end of the selected ororpharyngeal model. After the dose is emitted from the inhaler, the analysis and assay of throat deposition and material passing beyond the throat was used to derive the nominal, minimum, and maximum predicted total emitted dose. All Subjects Population. Only those participants available at the specified time point were analyzed. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    VI 25 µg
    Number of subjects analysed
    25 [79]
    Units: micrograms
    arithmetic mean (standard deviation)
        Nominal TED
    20.28 ± 0.177
        Minimum TED
    20.24 ± 0.188
        Maximum TED
    20.31 ± 0.173
    Notes
    [79] - All Subjects Population. Only those participants available at the specified time point were analyzed
    No statistical analyses for this end point

    Secondary: Ex-throat dose (ETD) and ETD <2 microns on Day 1 and Day 14 of the respective treatment period

    Close Top of page
    End point title
    Ex-throat dose (ETD) and ETD <2 microns on Day 1 and Day 14 of the respective treatment period
    End point description
    The ex-throat dose (ETD) and the “nominal ETD” is the mass (micrograms) of active investigational material that passes beyond the throat, nominal being the mean.The recorded inhalation profiles of the participants and the mouth-throat (oropharyngeal) models of the sizes that approximated to pharyngometry measurements of the participants were used in conjunction with the electronic Lung (eLung) for in vitro assessment. The eLung is a breathing simulator that replicates the selected inhalation profile with an active inhaler placed at the lips end of the selected ororpharyngeal model. After the dose is emitted from the inhaler, the analysis and assay of throat deposition and material passing beyond the throat was used to derive the nominal, minimum, and maximum predicted ETD and ETD <2 microns.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14 of the respective treatment period (up to Study Day 49)
    End point values
    VI 25 µg
    Number of subjects analysed
    15 [80]
    Units: micrograms
    arithmetic mean (standard deviation)
        Nominal ETD
    9 ± 0.697
        Minimum ETD
    8.94 ± 0.652
        Maximum ETD
    9.06 ± 0.747
        ETD <2 microns
    4.19 ± 1.079
        Minimum ETD <2 microns
    4.1 ± 1.011
        Maximum ETD <2 microns
    4.29 ± 1.157
    Notes
    [80] - All Subjects Population. Only those participants available at the specified time point were analyzed
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    On-treatment adverse events were reported.
    Adverse event reporting additional description
    Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    All participants who received matching placebo in one or both of the two 14-day treatment periods. Matching placebo was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.

    Reporting group title
    VI 25 µg
    Reporting group description
    All participants who received VI 25µg in one or both of the two 14-day treatment periods. Inhaled VI 25µg was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.

    Serious adverse events
    Placebo VI 25 µg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    Placebo VI 25 µg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 26 (23.08%)
    9 / 27 (33.33%)
    Injury, poisoning and procedural complications
    Limb Injury
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Spinal Column Injury
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Cardiac disorders
    Sinus Bradycardia
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 27 (7.41%)
         occurrences all number
    2
    2
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Chest Pain
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Conversion Disorder
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Disorientation
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    0
    3
    Otitis media
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2020 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA