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    Clinical Trial Results:
    A Double-Blind, Double-Dummy, Randomised, Placebo- And Active-Controlled, Three-Way Crossover Study to Evaluate the Effect of Budesonide/Formoterol Spiromax® 80/4.5 mcg Inhalation Powder and Symbicort® Turbohaler® 100/6 mcg on the Short-Term Lower Leg Growth Rate in Prepubescent Children With Persistent Asthma

    Summary
    EudraCT number
    2010-019082-29
    Trial protocol
    DK  
    Global end of trial date
    26 Jan 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Mar 2019
    First version publication date
    23 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BFS-AS-305
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Branded Pharmaceutical Products R&D, Inc.
    Sponsor organisation address
    74 NW, 176th Street, Miami, FL, United States, 33169
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc., 001 215-591-3000, info.eraclinical@teva.de
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc., 001 215-591-3000, info.eraclinical@teva.de
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Jan 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jan 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate the non-inferiority of Budesonide/Formoterol Spiromax® 80/4.5 micrograms (mcg) Inhalation Powder (Budesonide Formoterol [BF] Spiromax) relative to Symbicort® Turbohaler® 100/6 mcg (Symbicort Turbohaler) on short-term growth rate of the right lower leg as measured by knemometry in prepubescent children with persistent asthma.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, clinical research guidelines established by the US Code of Federal Regulations (Title 21, CFR Parts 50, 56 and 312), European Union (EU) Directives (where applicable), with Good Clinical Practice (GCP) requirements described in the current revision of International Conference on Harmonization (ICH) of Technical Requirements of Pharmaceuticals for Human Use guidelines, and in accordance with local regulations and legal requirements. The study was conducted with due attention to the rights of children. The interest of the children always prevailed over those of science and society.
    Background therapy
    Participants were allowed to take short-acting beta agonist (SABA) therapy throughout the study (during 2-week run-in period, 2-week wash-out periods, and 3 treatment periods [2 weeks each]).
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Sep 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
    Denmark: 77
    Worldwide total number of subjects
    77
    EEA total number of subjects
    77
    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)
    77
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 81 participants were screened, of which 4 participants were screen failures. A total of 77 participants were randomized and treated in 1 of the 6 different treatment sequences, after the 14-day run-in period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Arm title
    All Participants
    Arm description
    All participants were randomized to 1 of 6 treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA), each of which was comprised of the same 3 interventions (A, B, and C). Treatment A consisted of 2 oral inhalations of Budesonide 80 mcg/Formoterol 4.5 mcg (BF SPIROMAX®) (active treatment) in morning (AM) and 2 oral inhalations in evening (PM) along with 2 oral inhalations of Turbohaler placebo both in AM and PM. Treatment B consisted of 2 oral inhalations of Budesonide 100 mcg/Formoterol 6 mcg (Symbicort® Turbohaler®) (comparator) in AM and 2 oral inhalations in PM along with 2 oral inhalations of Spiromax placebo both in AM and PM. Treatment C consisted of 2 oral inhalations of Spiromax placebo in AM and 2 oral inhalations in PM along with 2 oral inhalations of Turbohaler placebo both in AM and PM. The study included 3 treatment periods which were 14 days (+/-4 days) each. Treatment Periods 1 and 2 were followed by a 14-day Washout Period (+/-4 days).
    Arm type
    Experimental

    Investigational medicinal product name
    BF SPIROMAX®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Budesonide 80 mcg and formoterol fumarate dihydrate 4.5 mcg; administered as oral inhalations.

    Investigational medicinal product name
    Symbicort® Turbohaler®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Budesonide 100 mcg and formoterol fumarate dihydrate 6 mcg; administered as oral inhalations.

    Investigational medicinal product name
    Spiromax Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Spiromax placebo administered as oral inhalations.

    Investigational medicinal product name
    Turbohaler Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Turbohaler placebo administered as oral inhalations.

    Number of subjects in period 1
    All Participants
    Started
    77
    Received at least 1 dose of study drug
    77
    Intent-to-treat (ITT) population
    76
    Completed
    73
    Not completed
    4
         Adverse event
    1
         Consent withdrawn by subject
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    All Participants
    Reporting group description
    All participants were randomized to 1 of 6 treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA), each of which was comprised of the same 3 interventions (A, B, and C). Treatment A consisted of 2 oral inhalations of Budesonide 80 mcg/Formoterol 4.5 mcg (BF SPIROMAX®) (active treatment) in morning (AM) and 2 oral inhalations in evening (PM) along with 2 oral inhalations of Turbohaler placebo both in AM and PM. Treatment B consisted of 2 oral inhalations of Budesonide 100 mcg/Formoterol 6 mcg (Symbicort® Turbohaler®) (comparator) in AM and 2 oral inhalations in PM along with 2 oral inhalations of Spiromax placebo both in AM and PM. Treatment C consisted of 2 oral inhalations of Spiromax placebo in AM and 2 oral inhalations in PM along with 2 oral inhalations of Turbohaler placebo both in AM and PM. The study included 3 treatment periods which were 14 days (+/-4 days) each. Treatment Periods 1 and 2 were followed by a 14-day Washout Period (+/-4 days).

    Reporting group values
    All Participants Total
    Number of subjects
    77 77
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    8.6 ± 1.51 -
    Gender Categorical
    Units: Subjects
        Female
    31 31
        Male
    46 46

    End points

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    End points reporting groups
    Reporting group title
    All Participants
    Reporting group description
    All participants were randomized to 1 of 6 treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA), each of which was comprised of the same 3 interventions (A, B, and C). Treatment A consisted of 2 oral inhalations of Budesonide 80 mcg/Formoterol 4.5 mcg (BF SPIROMAX®) (active treatment) in morning (AM) and 2 oral inhalations in evening (PM) along with 2 oral inhalations of Turbohaler placebo both in AM and PM. Treatment B consisted of 2 oral inhalations of Budesonide 100 mcg/Formoterol 6 mcg (Symbicort® Turbohaler®) (comparator) in AM and 2 oral inhalations in PM along with 2 oral inhalations of Spiromax placebo both in AM and PM. Treatment C consisted of 2 oral inhalations of Spiromax placebo in AM and 2 oral inhalations in PM along with 2 oral inhalations of Turbohaler placebo both in AM and PM. The study included 3 treatment periods which were 14 days (+/-4 days) each. Treatment Periods 1 and 2 were followed by a 14-day Washout Period (+/-4 days).

    Subject analysis set title
    BF Spiromax
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Budesonide 80 mcg/Formoterol 4.5 mcg, two oral inhalations in morning and two oral inhalations in evening in each treatment period.

    Subject analysis set title
    Symbicort Turbohaler
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Budesonide 100 mcg/Formoterol 6 mcg, two oral inhalations in morning and two oral inhalations in evening in each treatment period.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Spiromax placebo or Turbohaler placebo, two oral inhalations in morning and two oral inhalations in evening in each treatment period.

    Primary: Short-Term Lower Leg Growth Rate (LLGR) of The Right Lower Leg

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    End point title
    Short-Term Lower Leg Growth Rate (LLGR) of The Right Lower Leg
    End point description
    Short-term LLGR was measured by knemometry of the right lower leg after 2 weeks of treatment, and was calculated for each participant and for each treatment period in millimeters per week (mm/week). Four measurements were taken at each visit, with summaries and analysis based on the mean of the last three results. The LLGR was then determined from the change in growth measurement and number of days in each period; that is, LLGR (mm/week) = ([length in mm (end) - length in mm (start)]/[date (end) - date (start)] + 1) * 7. Per-protocol (PP) population included all data from the ITT population (included all randomised participants who received at least one dose of randomised study medication and had at least one post-baseline assessment.) obtained prior to experiencing major protocol violations.
    End point type
    Primary
    End point timeframe
    Treatments periods 1, 2, and 3 (each treatment period = 2 weeks)
    End point values
    BF Spiromax Symbicort Turbohaler Placebo
    Number of subjects analysed
    70
    70
    70
    Units: mm/week
        arithmetic mean (standard deviation)
    0.052 ± 0.3396
    0.134 ± 0.3605
    0.247 ± 0.3901
    Statistical analysis title
    BF Spiromax vs. Symicort Turbohaler
    Statistical analysis description
    Actual number of participants analysed=70. Analysis was performed using ANOVA model with fixed effects of treatment, sequence, and period, a random effect of participant within sequence. Non-inferiority was demonstrated if the lower limit of the 95% two-sided confidence interval for the treatment difference in the short-term LLGR (BF Spiromax minus Symbicort Turbohaler) was greater than -0.200 mm/week.
    Comparison groups
    BF Spiromax v Symbicort Turbohaler
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Parameter type
    Least square (LS) mean difference
    Point estimate
    -0.086
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.203
         upper limit
    0.032

    Secondary: Change From Period-Specific Baseline in Daily Trough Morning (AM) and Evening (PM) Peak Expiratory Flow (PEF) Rate at End of Each Treatment Period

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    End point title
    Change From Period-Specific Baseline in Daily Trough Morning (AM) and Evening (PM) Peak Expiratory Flow (PEF) Rate at End of Each Treatment Period
    End point description
    PEF was determined twice daily, in AM and in PM, before administration of study medications or rescue bronchodilator during run-in period and throughout study. AM PEF was calculated as daily average of AM PEF over the previous 7 days prior to beginning of each treatment period with at least 4 days of non-missing values. The period-specific baseline trough AM PEF was calculated as daily average of AM PEF over each 2-week treatment period with at least 4 days of non-missing values. If non-missing days in each period was less than 4 days, the values were treated as missing. PM PEF and period-specific baseline trough PM PEF was calculated in a manner similar to AM PEF. PP population included all data from ITT population (included all randomised participants who received at least 1 dose of randomised study medication and had at least 1 post-baseline assessment.) obtained prior to experiencing major protocol violations. Here, "n" = number of participants evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline, at end of treatment period 1, 2 and 3 (each treatment period = 2 weeks)
    End point values
    BF Spiromax Symbicort Turbohaler Placebo
    Number of subjects analysed
    70
    70
    70
    Units: L/min
    arithmetic mean (standard deviation)
        AM PEF: Change at Period 1 (n=22,23,25)
    18.74 ± 24.064
    17.13 ± 17.325
    -1.98 ± 15.764
        AM PEF: Change at Period 2 (n=25,24,19)
    15.45 ± 17.967
    13.50 ± 20.372
    0.38 ± 13.293
        AM PEF: Change at Period 3 (n=21,22,25)
    23.34 ± 21.007
    17.60 ± 13.274
    2.14 ± 11.547
        PM PEF: Change at Period 1 (n=23,24,25)
    16.88 ± 24.914
    16.80 ± 16.895
    -2.30 ± 15.351
        PM PEF: Change at Period 2 (n=25,24,19)
    14.48 ± 17.354
    15.62 ± 23.915
    2.48 ± 18.410
        PM PEF: Change at Period 3 (n=21,22,25)
    17.88 ± 19.827
    15.19 ± 14.886
    2.78 ± 12.445
    No statistical analyses for this end point

    Secondary: Change From Period-Specific Baseline in Percentage of Rescue-Free Days at End of Each Treatment Period

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    End point title
    Change From Period-Specific Baseline in Percentage of Rescue-Free Days at End of Each Treatment Period
    End point description
    Participants recorded their use of rescue medication twice daily (AM and PM) before intake of study medications. For the purpose of this study, a "day" was the combination of AM and PM in a 24-hour period. Percentage of days rescue medication taken was calculated as: (Number of days with puffs = 0 / Number of non-missing days (>=4 days)*100. Period-specific baseline was defined as percentage of rescue-free days over the last 7 days prior to the beginning of each treatment period with at least 4 days of non-missing values. A non-missing day was defined as a day in which rescue medication records were non-missing in either the AM or PM or both. PP population included all data from the ITT population (included all randomised participants who received at least one dose of randomised study medication and had at least one post-baseline assessment.) obtained prior to experiencing major protocol violations. Here, "n" signifies number of participants evaluable at specified treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline, at end of treatment period 1, 2 and 3 (each treatment period = 2 weeks)
    End point values
    BF Spiromax Symbicort Turbohaler Placebo
    Number of subjects analysed
    70
    70
    70
    Units: percentage of days
    arithmetic mean (standard deviation)
        Change at Period 1 (n = 23, 24, 25)
    1.08 ± 18.109
    7.00 ± 24.374
    10.91 ± 31.050
        Change at Period 2 (n= 25, 24, 19)
    3.30 ± 17.391
    15.60 ± 38.770
    2.57 ± 18.534
        Change at Period 3 (n= 21, 22, 26)
    9.37 ± 18.378
    11.90 ± 29.572
    9.35 ± 25.633
    No statistical analyses for this end point

    Secondary: Change From Period-Specific Baseline in Inspiratory Flow Rate at End of Each Treatment Period

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    End point title
    Change From Period-Specific Baseline in Inspiratory Flow Rate at End of Each Treatment Period
    End point description
    Period-specific baseline was defined as the average of the 3 inspiratory flow rate obtained at the beginning of each treatment period. PP population included all data from the ITT population (included all randomised participants who received at least one dose of randomised study medication and had at least one post-baseline assessment.) obtained prior to experiencing major protocol violations. Since this was a crossover study, a participant could be excluded from one treatment period, but still be included in the PP population for the other treatment periods. Here, "n" signifies number of participants evaluable at specified treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline, at end of treatment period 1, 2 and 3 (each treatment period =2 weeks)
    End point values
    BF Spiromax Symbicort Turbohaler Placebo
    Number of subjects analysed
    70
    70
    70
    Units: liters/minute (L/min)
    arithmetic mean (standard deviation)
        Change at the end of Period 1 (n=23, 24, 25)
    -4.49 ± 31.247
    8.61 ± 25.517
    -9.31 ± 28.642
        Change at the end of Period 2 (n=25, 24, 19)
    4.87 ± 14.521
    9.37 ± 30.577
    8.33 ± 21.766
        Change at the end of Period 3 (n=22, 22, 26)
    -11.52 ± 25.515
    -12.65 ± 21.092
    -13.33 ± 22.151
    No statistical analyses for this end point

    Other pre-specified: 24-Hour Urinary Cortisol (UC) Excretion

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    End point title
    24-Hour Urinary Cortisol (UC) Excretion
    End point description
    UC population included all randomised participants who received at least one dose of randomised study medication, and whose urine samples did not have confounding factors that would affect the interpretation of the results. Here, "n" signifies number of participants evaluable at specified treatment period.
    End point type
    Other pre-specified
    End point timeframe
    Treatment periods 1, 2, and 3 (each treatment period = 2 weeks)
    End point values
    BF Spiromax Symbicort Turbohaler Placebo
    Number of subjects analysed
    18
    16
    17
    Units: nanomols/liter (nmol/L)
    arithmetic mean (standard deviation)
        Period 1 (n=8, 4, 6)
    32.14 ± 13.480
    25.75 ± 16.144
    47.63 ± 31.845
        Period 2 (n=4, 7, 4)
    25.05 ± 10.440
    31.99 ± 15.159
    25.40 ± 14.424
        Period 3 (n=6, 5, 7)
    22.48 ± 20.213
    26.56 ± 10.637
    50.84 ± 26.204
    No statistical analyses for this end point

    Other pre-specified: 24-Hour Urinary Cortisol/Creatinine Ratio

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    End point title
    24-Hour Urinary Cortisol/Creatinine Ratio
    End point description
    UC population included all randomised participants who received at least one dose of randomised study medication, and whose urine samples did not have confounding factors that would affect the interpretation of the results. Here, "n" signifies number of participants evaluable at specified treatment period.
    End point type
    Other pre-specified
    End point timeframe
    Treatment periods 1, 2, and 3 (each treatment period = 2 weeks)
    End point values
    BF Spiromax Symbicort Turbohaler Placebo
    Number of subjects analysed
    18
    16
    17
    Units: ratio
    arithmetic mean (standard deviation)
        Period 1 (n=8, 4, 6)
    9.18 ± 3.917
    10.33 ± 6.370
    8.81 ± 3.923
        Period 2 (n=4, 7, 4)
    14.25 ± 6.185
    13.74 ± 8.691
    5.63 ± 2.326
        Period 3 (6, 5, 5)
    9.12 ± 7.411
    7.50 ± 5.319
    19.38 ± 13.445
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization until end of third treatment period (in total up to approximately 10 weeks)
    Adverse event reporting additional description
    Safety population included all randomised participants who received at least one dose of randomised study medication.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    BF Spiromax
    Reporting group description
    Budesonide 80 mcg/Formoterol 4.5 mcg, two oral inhalations in morning and two oral inhalations in evening in each treatment period.

    Reporting group title
    Placebo
    Reporting group description
    Spiromax placebo or Turbohaler placebo, two oral inhalations in morning and two oral inhalations in evening in each treatment period.

    Reporting group title
    Symbicort Turbohaler
    Reporting group description
    Budesonide 100 mcg/Formoterol 6 mcg, two oral inhalations in morning and two oral inhalations in evening in each treatment period.

    Serious adverse events
    BF Spiromax Placebo Symbicort Turbohaler
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 75 (1.33%)
    0 / 75 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 75 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    BF Spiromax Placebo Symbicort Turbohaler
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 74 (1.35%)
    6 / 75 (8.00%)
    2 / 75 (2.67%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 74 (1.35%)
    6 / 75 (8.00%)
    2 / 75 (2.67%)
         occurrences all number
    1
    7
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Nov 2010
    The purpose of amendment was to remove blood pressure (BP) as a study assessment. BP was included as a study assessment as it was a non-invasive measure and was not anticipated to be problematic to obtain. However, in attempting to obtain BP measurements, the Principal Investigator noted that the study participants were not used to having their BP measured. This caused high levels of anxiety about the BP measurements by many of the study participants with the result that BP measurements may have been artificially elevated in many participants. Anxiety about the BP measurements by many of the study participants was particularly evident during the baseline BP measurements. However, by the time Protocol Amendment 1 had been submitted to the Danish Medicines Agency, the Principal Investigator confirmed that study participants had become accustomed to the BP assessment process and that study participants were no longer anxious about their BP measurements. The Principal Investigator also confirmed that all study participants and their parents were agreeable to have BP assessments for the remainder of the study. Therefore, the request to the Danish Medicines Agency to authorise Protocol Amendment 1 was withdrawn and was not implemented. The study continued using the Final Version, Revision 1 of the Protocol which was dated 21 Sep 2010.

    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
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