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    Clinical Trial Results:
    A double-blind randomised multi-centre, placebo-controlled trial of combined ACE-inhibitor and beta-blocker therapy in preventing the development of cardiomyopathy in genetically characterised males with DMD without echo-detectable left ventricular dysfunction

    Summary
    EudraCT number
    2007-005932-10
    Trial protocol
    GB  
    Global end of trial date
    23 Mar 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Dec 2019
    First version publication date
    02 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NCTU:ISRCTN50395346
    Additional study identifiers
    ISRCTN number
    ISRCTN50395346
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    The Newcastle upon Tyne Hospitals NHS Foundation Trust
    Sponsor organisation address
    NJRO, Level 1, Regent Point, Regent Farm Road, Gosforth, Newcastle upon Tyne, United Kingdom, NE3 3HD
    Public contact
    Sean Scott, The Newcastle upon Tyne Hospitals NHS Foundation Trust, tnu-tr.sponsormanagement@nhs.net
    Scientific contact
    Sean Scott, The Newcastle upon Tyne Hospitals NHS Foundation Trust, tnu-tr.sponsormanagement@nhs.net
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether the introduction of ACE-inhibitor (perindopril) combined with beta-blocker therapy (bisoprolol), before the onset of echo-detectable left ventricular dysfunction, can delay the age of onset and/or slow the rate of progression of cardiomyopathy in males with DMD.
    Protection of trial subjects
    None
    Background therapy
    None
    Evidence for comparator
    Placebo control was chosen in order to maintain power and a simple trial design; hence, the benefits of combination therapy (ACE-inhibitor and beta-blocker) against placebo were evaluated in a two-arm trial.
    Actual start date of recruitment
    26 May 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 85
    Worldwide total number of subjects
    85
    EEA total number of subjects
    85
    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)
    74
    Adolescents (12-17 years)
    11
    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
    The recruitment period ran from 25 May 2011 to 22 January 2015, at five NHS hospital sites in the United Kingdom. Sites were in Newcastle upon Tyne, London, Liverpool, Birmingham and Oxford.

    Pre-assignment
    Screening details
    Site trial staff screened DMD patients who currently attend neurology or equivalent clinics for supervision of their symptoms, or have regular schedules for cardiac surveillance, for potential participants. Screening logs were kept at each site, recording patient details, satisfaction of eligibility criteria, and reasons for exclusion.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Assessor, Subject
    Blinding implementation details
    Trial IMP tablets were over-encapsulated, and accompanied by matched placebo, to establish the blind from trial start, in bottles numbered according to the blinded randomisation schedule. Sealed codebreak envelopes were stored in the Pharmacy/ISF, and opened only in an emergency. Unblinding was notified to the trial co-ordinating team, and a record kept in the TMF and ISF. The blind was maintained until all trial data were collected and the database locked, when participants were unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment
    Arm description
    Combined capsule containing 2 mg perindopril and 1.25 mg bisoprolol
    Arm type
    Experimental

    Investigational medicinal product name
    Bisoprolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Boys up to 30 kg body weight at baseline - Months 2-60 (or study end date or until their bodyweight increases to 30 kg or over): one capsule per day, containing 1.25 mg bisoprolol 1.25 mg Boys 30 kg or over body weight at baseline - Months 2-60 (or study end date): Change to maintenance dosage of two capsules per day, containing 2.5 mg bisoprolol Boys up to 30 kg body weight at baseline but whose body weight increases to 30 kg or over during the trial – From follow-up appointment where weight increased to 30 kg or over to month 60 (or study end date): Change to maintenance dosage of two capsules per day, containing 2.5 mg bisoprolol

    Investigational medicinal product name
    Perindopril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Boys up to 30 kg body weight at baseline - Months 2-60 (or study end date or until their bodyweight increases to 30 kg or over): Combined capsule containing 2 mg perindopril Boys 30 kg or over body weight at baseline - Months 2-60 (or study end date): Change to maintenance dosage of two capsules containing 4 mg perindopril Boys up to 30 kg body weight at baseline but whose body weight increases to 30 kg or over during the trial – From follow-up appointment where weight increased to 30 kg or over to month 60 (or study end date): Change to maintenance dosage of two capsules containing 4 mg perindopril

    Arm title
    Placebo
    Arm description
    Matching placebo
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Boys up to 30 kg body weight at baseline - Months 2-60 (or study end date or until their bodyweight increases to 30 kg or over): Capsule containing matched placebo Boys 30 kg or over body weight at baseline - Months 2-60 (or study end date): Change to maintenance dosage of two capsules of matched placebo Boys up to 30 kg body weight at baseline but whose body weight increases to 30 kg or over during the trial – From follow-up appointment where weight increased to 30 kg or over to month 60 (or study end date): Change to maintenance dosage of two capsules of matched placebo

    Number of subjects in period 1
    Treatment Placebo
    Started
    42
    43
    Completed
    42
    43
    Period 2
    Period 2 title
    36 months' participation
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Trial IMP tablets were over-encapsulated, and accompanied by matched placebo, to establish the blind from trial start, in bottles numbered according to the blinded randomisation schedule. Sealed codebreak envelopes were stored in the Pharmacy/ISF, and opened only in an emergency. Unblinding was notified to the trial co-ordinating team, and a record kept in the TMF and ISF. The blind was maintained until all trial data were collected and the database locked, when participants were unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment
    Arm description
    Combined capsule containing 2 mg perindopril and 1.25 mg bisoprolol
    Arm type
    Experimental

    Investigational medicinal product name
    Bisoprolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Boys up to 30 kg body weight at baseline - Months 2-60 (or study end date or until their bodyweight increases to 30 kg or over): one capsule per day, containing 1.25 mg bisoprolol 1.25 mg Boys 30 kg or over body weight at baseline - Months 2-60 (or study end date): Change to maintenance dosage of two capsules per day, containing 2.5 mg bisoprolol Boys up to 30 kg body weight at baseline but whose body weight increases to 30 kg or over during the trial – From follow-up appointment where weight increased to 30 kg or over to month 60 (or study end date): Change to maintenance dosage of two capsules per day, containing 2.5 mg bisoprolol

    Investigational medicinal product name
    Perindopril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Boys up to 30 kg body weight at baseline - Months 2-60 (or study end date or until their bodyweight increases to 30 kg or over): Combined capsule containing 2 mg perindopril Boys 30 kg or over body weight at baseline - Months 2-60 (or study end date): Change to maintenance dosage of two capsules containing 4 mg perindopril Boys up to 30 kg body weight at baseline but whose body weight increases to 30 kg or over during the trial – From follow-up appointment where weight increased to 30 kg or over to month 60 (or study end date): Change to maintenance dosage of two capsules containing 4 mg perindopril

    Arm title
    Placebo
    Arm description
    Placebo
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Boys up to 30 kg body weight at baseline - Months 2-60 (or study end date or until their bodyweight increases to 30 kg or over): Capsule containing matched placebo Boys 30 kg or over body weight at baseline - Months 2-60 (or study end date): Change to maintenance dosage of two capsules of matched placebo Boys up to 30 kg body weight at baseline but whose body weight increases to 30 kg or over during the trial – From follow-up appointment where weight increased to 30 kg or over to month 60 (or study end date): Change to maintenance dosage of two capsules of matched placebo

    Number of subjects in period 2
    Treatment Placebo
    Started
    42
    43
    Completed
    35
    30
    Not completed
    7
    13
         Lost to follow-up
    7
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    Combined capsule containing 2 mg perindopril and 1.25 mg bisoprolol

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo

    Reporting group values
    Treatment Placebo Total
    Number of subjects
    42 43 85
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    The subject population was children between the ages of five and 12 .
    Units: years
        arithmetic mean (standard deviation)
    9.6 ± 1.8 9.7 ± 2.0 -
    Gender categorical
    Subjects were male.
    Units: Subjects
        Female
    0 0 0
        Male
    42 43 85
    Genetic mutation type
    Type of genetic mutation that participant exhibits.
    Units: Subjects
        None identified/misssing
    9 14 23
        Deletion
    25 15 40
        Duplication
    2 3 5
        Point mutation
    4 7 11
        Other
    2 4 6
    Enrolling centre
    Trial site/centre at which the participant was recruited.
    Units: Subjects
        Newcastle
    14 14 28
        London
    23 22 45
        Liverpool
    5 5 10
        Birmingham
    0 1 1
        Oxford
    0 1 1
    Body surface area
    Body surface area of participant.
    Units: Sqrt(weight(kg)*height(cm)/3600)
        arithmetic mean (standard deviation)
    32.2 ± 59.6 31.9 ± 58.1 -

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    Combined capsule containing 2 mg perindopril and 1.25 mg bisoprolol

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo
    Reporting group title
    Treatment
    Reporting group description
    Combined capsule containing 2 mg perindopril and 1.25 mg bisoprolol

    Reporting group title
    Placebo
    Reporting group description
    Placebo

    Primary: 36 months' participation

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    End point title
    36 months' participation
    End point description
    End point description: The primary outcome measure was change in left ventricular ejection fraction (LVEF %), compared to baseline after a minimum of three years of combination therapy or placebo. To assess the robustness of ejection fraction result, similar comparisons will be made for parameters of left ventricular end-systolic dimension, wall motion index and left ventricular fractional shortening (%) and mitral flow to left ventricular tissue Doppler ratios (E/E’ ratios).
    End point type
    Primary
    End point timeframe
    36 months post-randomisation.
    End point values
    Treatment Placebo
    Number of subjects analysed
    33
    24
    Units: range 0 to 45
    33
    24
    Statistical analysis title
    LV Ejection Fraction
    Statistical analysis description
    LV Ejection Fraction (LVEF) at 36 months from baseline (post-randomisation).
    Comparison groups
    Treatment v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -2.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.2
         upper limit
    1.1
    Statistical analysis title
    LV end systolic dimensions
    Statistical analysis description
    LV end systolic dimensions at 36 months from baseline.
    Comparison groups
    Treatment v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    ANCOVA
    Parameter type
    Median difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.1
    Statistical analysis title
    LV end diastolic dimensions
    Statistical analysis description
    LV end diastolic dimensions at 36 months from baseline.
    Comparison groups
    Treatment v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    ANCOVA
    Parameter type
    Median difference (net)
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    0.1
    Statistical analysis title
    LV Ejection Fraction
    Statistical analysis description
    LV Ejection Fraction (LVEF) up to 36 months
    Comparison groups
    Treatment v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    ANOVA
    Confidence interval
    Statistical analysis title
    LV fractional shortening
    Statistical analysis description
    LV fractional shortening up to 36 months
    Comparison groups
    Treatment v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    ANOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All non-SAEs/SARs occurring during drug treatment were reported on the eCRF system within four weeks of the form being due.
    Adverse event reporting additional description
    All Adverse Events were recorded. PIs were responsible for managing all AEs/ARs according to local protocols.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Treatment
    Reporting group description
    Participants receiving active treatment.

    Reporting group title
    Placebo
    Reporting group description
    Participants receiving placebo.

    Serious adverse events
    Treatment Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Injury, poisoning and procedural complications
    Fracture
    Additional description: The participant suffered fractures of his right and left femurs.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Knee injury
    Additional description: The participant suffered a knee injury, and was put in a plaster cast.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Palpitations
    Additional description: The participant suffered from palpitations.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fat embolism
    Additional description: The participant suffered a fat embolism.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pericarditis
    Additional description: The participant suffered from acute pericarditis.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Overdose
    Additional description: The participant suffered an accidental overdose of lisinopril (not trial medication).
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chest pain
    Additional description: Participant suffered chest pain.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
    Additional description: The participant suffered from pneumonia.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infection
    Additional description: The participant suffered from a chest infection.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lower respiratory tract infection
    Additional description: The participant suffered from a lower respiratory tract infection.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory tract infection
    Additional description: The participant suffered from a respiratory tract infection (with lethargy, tiredness and cough), and had a delayed recovery.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Fall
    Additional description: Fall from wheelchair with initial recovery, but subsequent seizure, apnoea and failure of resuscitation in A&E.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Headache
    Additional description: The participant suffered with headaches, nausea and visual disturbance.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lethargy
    Additional description: The participant suffered from lethargy and was hospitalised.
         subjects affected / exposed
    11 / 42 (26.19%)
    11 / 43 (25.58%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Adverse reaction
    Additional description: The participant suffered an adverse reaction to bisphosphonates, specifically zoledronic acid (not the trial medication).
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    Additional description: The participant suffered from abdominal pain.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastroenteritis
    Additional description: The participant suffered from gastroenteritis.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastric ulcer
    Additional description: The participant suffered with superficial gastric ulceration.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Constipation
    Additional description: The participant suffered from severe constipation.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    ICU admission
    Additional description: The participant suffered musculoskeletal symptoms due to his Duchenne muscular dystrophy, and was admitted to the ICU.
         subjects affected / exposed
    11 / 42 (26.19%)
    13 / 43 (30.23%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Hypertension
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Surgical and medical procedures
    Cardiac catheterisation
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Planned hospital admission
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Verruca
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Hay fever
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Sickness
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Adverse reaction
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Constitutional symptoms
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Pyrexia
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Stomach pain, sore throat
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Behaviour disorder
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Insomnia
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Bite
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Fall
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Fat embolism
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Fracture
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Sprained ankle
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Foot injury
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Knee injury
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Cardiac disorders
    Chest pain, dyspnoea
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Palpitations
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Pericarditis
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Cardiac symptoms
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Increased heart rate
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Respiratory, thoracic and mediastinal disorders
    Cold
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Coryzal symptoms
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Cough
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Lower respiratory tract infection
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Sore throat
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Upper respiratory tract infection
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Chest pain
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Respiratory infection
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Nervous system disorders
    Fainting
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Headache
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Migraine
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Dizziness
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Lethargy
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Eye disorders
    Eye infection
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Eyes red, itchy, swollen
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Ear and labyrinth disorders
    Ear infection
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Blood in stools
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Colitis
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Diarrhoea
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Heartburn
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Stomach ache
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Vomiting
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Appendicitis perforated
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Skin and subcutaneous tissue disorders
    Itching
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Pressure sore
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Skin condition
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Pruritus
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Rash
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Neck pain
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Tight achilles tendon
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Knee pain
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Leg pain
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Infections and infestations
    Flu
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Oral thrush
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Pneumonia
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Throat infection
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Toe infection
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Chest infection
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Infection
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Ingrowing nail
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120
    Tonsillitis
         subjects affected / exposed
    29 / 42 (69.05%)
    34 / 43 (79.07%)
         occurrences all number
    84
    120

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Mar 2010
    Personnel changes (Addition of Assistant Trial Manager).

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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