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    Clinical Trial Results:
    A Multi-Center, Open-Label Study Evaluating Safety and Clinical Outcomes in Hunter Syndrome subjects 5 Years of Age and Younger Receiving Idursulfase Enzyme Replacement Therapy

    Summary
    EudraCT number
    		 2007-006044-22
    Trial protocol
    		 PL  
    Global end of trial date
    08 Jul 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Sep 2018
    First version publication date
    24 Jun 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HGT-ELA-038
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00607386
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire Human Genetic Therapies, Inc. (Shire HGT)
    Sponsor organisation address
    300 Shire Way, Lexington , MA 02421, United States,
    Public contact
    Arian Pano, Shire HGT, apano@shire.com
    Scientific contact
    Arian Pano, Shire HGT, apano@shire.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Jul 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jul 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the safety of once-weekly dosing of idursulfase (Elaprase®) 0.5 milligram per kilogram (mg/kg) administered by intravenous (IV) infusion for male Hunter syndrome subjects less than or equal to (<=) 5 years old.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with good clinical practice and applicable regulatory requirements. Known instances of nonconformance were documented and were not considered to have an impact on the overall conclusions of this study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Dec 2007
    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
    Taiwan: 3
    Country: Number of subjects enrolled
    Brazil: 15
    Country: Number of subjects enrolled
    Poland: 12
    Worldwide total number of subjects
    30
    EEA total number of subjects
    12
    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)
    4
    Children (2-11 years)
    26
    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 30 subjects were enrolled of which 28 subjects received study drug.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Idursulfase
    Arm description
    		 Open-label treatment with idursulfase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Idursulfase
    Investigational medicinal product code
    Other name
    Elaprase
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Idursulfase was administered every week at a dose of 0.5 mg/kg by continuous IV infusion over a minimum of 3 hours. The dose of drug was calculated based on the subject’s weight at each visit. Subjects received their first treatment at Week 1 and every week thereafter for 1 year up to a maximum of 52 infusions for the duration of the study.

    Number of subjects in period 1
    		Idursulfase
    Started
    28
    Completed
    27
    Not completed
    1
         Physician decision
    1

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Idursulfase
    Reporting group description
    		 Open-label treatment with idursulfase

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Not all the enrolled subjects were treated with study drug. As baseline included only treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.
    Reporting group values
    		 Idursulfase Total
    Number of subjects
    		 28
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 4 ( 1.62 ) -
    Gender Categorical
    Units: subjects
        Male
    		 28 28
    Baseline Normalized Urinary Glycosaminoglycan (GAG) Level
    Units: micorgram/milligram creatinine
        arithmetic mean (standard deviation)
    		 738.3 ( 165.21 ) -

    End points

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    End points reporting groups
    Reporting group title
    Idursulfase
    Reporting group description
    		 Open-label treatment with idursulfase

    Subject analysis set title
    Pharmacokinetic (PK) Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All enrolled subjects who had at least one serum concentration measurement available.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All enrolled subjects who received at least one study dose (or any portion of a dose) of idursulfase.

    Primary: Safety Evaluation

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    End point title
    		 Safety Evaluation [1]
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Number of subjects with AEs occurred after start of study treatment until 30 days after the last infusion of idursulfase, were reported.
    End point type
    Primary
    End point timeframe
    From the start of study treatment until 30 days after the last infusion of idursulfase
    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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Idursulfase
    Number of subjects analysed
    28 [2]
    Units: subjects
    number (not applicable)
        Experienced at least one adverse event (AE)
    28
        Deaths
    0
        Discontinued due to an AE
    0
        Experienced at least one drug-related AE
    16
        Experienced at least one serious AE (SAE)
    13
        Experienced at least one severe AE
    2
        Experienced at least one infusion-related AE
    16
    Notes
    [2] - Safety population.
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline to Week 53 in Normalized Urinary Glycosaminoglycan (GAG) Levels

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    End point title
    		 Mean Change from Baseline to Week 53 in Normalized Urinary Glycosaminoglycan (GAG) Levels
    End point description
    Analysis of urinary GAG levels was performed at baseline, Week 18, Week 36, and Week 53 as an assessment of the pharmacodynamic effects of Elaprase (idursulfase). In the categories listed below, 'N' signifies the number of subjects evaluable for the timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 18, 36 and 53
    End point values
    		 Idursulfase
    Number of subjects analysed
    28 [3]
    Units: microgram/milligram creatinine
    arithmetic mean (standard deviation)
        Baseline (N=28)
    738.3 ( 165.21 )
        Change at Week 18 (N=27)
    -368 ( 165.44 )
        Change at Week 36 (N=27)
    -400.3 ( 180.27 )
        Change at Week 53 (N=27)
    -402.4 ( 162.13 )
    Notes
    [3] - Safety population.
    No statistical analyses for this end point

    Secondary: Single- and Repeat-Dose Pharmacokinetics - Maximum Observed Serum Concentration (Cmax)

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    End point title
    		 Single- and Repeat-Dose Pharmacokinetics - Maximum Observed Serum Concentration (Cmax)
    End point description
    In the categories listed below, “N” signifies the number of subjects evaluable for the timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 1 and 27
    End point values
    		 Idursulfase
    Number of subjects analysed
    27 [4]
    Units: nanogram per milliliter
    arithmetic mean (standard deviation)
        Week 1 (N=27)
    1333 ( 817 )
        Week 27 (N=19)
    1032 ( 590 )
    Notes
    [4] - PK population.
    No statistical analyses for this end point

    Secondary: Single- and Repeat-Dose Pharmacokinetics - Time of Maximum Observed Serum Concentration (Tmax)

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    End point title
    		 Single- and Repeat-Dose Pharmacokinetics - Time of Maximum Observed Serum Concentration (Tmax)
    End point description
    In the categories listed below, “N” signifies the number of subjects evaluable for the timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 1 and 27
    End point values
    		 Idursulfase
    Number of subjects analysed
    27 [5]
    Units: minutes
    arithmetic mean (standard deviation)
        Week 1 (N=27)
    163 ( 28 )
        Week 27 (N=19)
    167 ( 32 )
    Notes
    [5] - PK population.
    No statistical analyses for this end point

    Secondary: Single- and Repeat-Dose Pharmacokinetics - Area Under the Serum Concentration-Time Curve from Time 0 to the Final Time Point with a Concentration of at Least Lower Limit of Quantitation (AUClast)

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    End point title
    		 Single- and Repeat-Dose Pharmacokinetics - Area Under the Serum Concentration-Time Curve from Time 0 to the Final Time Point with a Concentration of at Least Lower Limit of Quantitation (AUClast)
    End point description
    In the categories listed below, “N” signifies the number of subjects evaluable for the timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 1 and 27
    End point values
    		 Idursulfase
    Number of subjects analysed
    27 [6]
    Units: minute*nanogram per milliliter
    arithmetic mean (standard deviation)
        Week 1 (N=27)
    196526 ( 71779 )
        Week 27 (N=19)
    174869 ( 109118 )
    Notes
    [6] - PK population.
    No statistical analyses for this end point

    Secondary: Single- and Repeat-Dose Pharmacokinetics - Area Under the Serum Concentration-Time Curve from Time 0 to Infinity (AUCinf)

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    End point title
    		 Single- and Repeat-Dose Pharmacokinetics - Area Under the Serum Concentration-Time Curve from Time 0 to Infinity (AUCinf)
    End point description
    In the categories listed below, “N” signifies the number of subjects evaluable for the timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 1 and 27
    End point values
    		 Idursulfase
    Number of subjects analysed
    26 [7]
    Units: minute*nanogram per milliliter
    arithmetic mean (standard deviation)
        Week 1 (N=26)
    224343 ( 76944 )
        Week 27 (N=18)
    201130 ( 117575 )
    Notes
    [7] - PK population with evaluable subjects for this endpoint.
    No statistical analyses for this end point

    Secondary: Single- and Repeat-Dose Pharmacokinetics - Elimination Half-Life (t1/2)

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    End point title
    		 Single- and Repeat-Dose Pharmacokinetics - Elimination Half-Life (t1/2)
    End point description
    t1/2 refers to the elimination of the drug. It is the time taken for the blood plasma concentration to reach half the concentration in the terminal phase of elimination. It is expressed in hours and derived from the terminal slope of the concentration versus time curve. In the categories listed below, “N” signifies the number of subjects evaluable for the timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 1 and 27
    End point values
    		 Idursulfase
    Number of subjects analysed
    26 [8]
    Units: minutes
    arithmetic mean (standard deviation)
        Week 1 (N=26)
    160 ( 69 )
        Week 27 (N=18)
    109 ( 43 )
    Notes
    [8] - PK population with evaluable subjects for this endpoint.
    No statistical analyses for this end point

    Secondary: Single- and Repeat-Dose Pharmacokinetics - Mean Residence Time from Time 0 to Infinity (MRTinf)

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    End point title
    		 Single- and Repeat-Dose Pharmacokinetics - Mean Residence Time from Time 0 to Infinity (MRTinf)
    End point description
    MRTinf is an average duration of the drug in the body from time zero to infinity, and is expressed in minutes. In the categories listed below, “N” signifies the number of subjects evaluable for the timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 1 and 27
    End point values
    		 Idursulfase
    Number of subjects analysed
    26 [9]
    Units: minutes
    arithmetic mean (standard deviation)
        Week 1 (N=26)
    153 ( 96 )
        Week 27 (N=18)
    127 ( 23 )
    Notes
    [9] - PK population with evaluable subjects for this endpoint.
    No statistical analyses for this end point

    Secondary: Single- and Repeat-Dose Pharmacokinetics - Clearance (CL)

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    End point title
    		 Single- and Repeat-Dose Pharmacokinetics - Clearance (CL)
    End point description
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. In the categories listed below, “N” signifies the number of subjects evaluable for the timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 1 and 27
    End point values
    		 Idursulfase
    Number of subjects analysed
    26 [10]
    Units: milliliter/minute/kilogram
    arithmetic mean (standard deviation)
        Week 1 (N=26)
    2.4 ( 0.7 )
        Week 27 (N=18)
    4.7 ( 5 )
    Notes
    [10] - PK population with evaluable subjects for this endpoint.
    No statistical analyses for this end point

    Secondary: Single- and Repeat-Dose Pharmacokinetics - Volume of Distribution at Steady State (Vss)

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    End point title
    		 Single- and Repeat-Dose Pharmacokinetics - Volume of Distribution at Steady State (Vss)
    End point description
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state. In the categories listed below, “N” signifies the number of subjects evaluable for the timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 1 and 27
    End point values
    		 Idursulfase
    Number of subjects analysed
    26 [11]
    Units: milliliter per kilogram
    arithmetic mean (standard deviation)
        Week 1 (N=26)
    394 ( 423 )
        Week 27 (N=18)
    551 ( 528 )
    Notes
    [11] - PK population with evaluable subjects for this endpoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of study treatment until 30 days after the last infusion of idursulfase
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.1
    Reporting groups
    Reporting group title
    Idursulfase
    Reporting group description
    		 Open-label treatment with idursulfase

    Serious adverse events
    		 Idursulfase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 28 (46.43%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Atonic seizures
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Microcytic anaemia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter site haematoma
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences causally related to treatment / all
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Food poisoning
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory distress
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin hypertrophy
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle contracture
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis media
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3.57%
    Non-serious adverse events
    		 Idursulfase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 28 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Hyperaemia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Haemorrhage
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    General disorders and administration site conditions
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Chest pain
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Malaise
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Pyrexia
         subjects affected / exposed
    25 / 28 (89.29%)
         occurrences all number
    59
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Allergic cough
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    3
    Choking
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Bronchospasm
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    3
    Dyspnoea
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Hypoxia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    16 / 28 (57.14%)
         occurrences all number
    45
    Pharyngolaryngeal pain
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Nasal congestion
         subjects affected / exposed
    6 / 28 (21.43%)
         occurrences all number
    9
    Lung infiltration
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Respiratory disorder
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Sleep apnoea syndrome
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    3
    Pulmonary hypertension
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    4
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Crying
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Agitation
         subjects affected / exposed
    4 / 28 (14.29%)
         occurrences all number
    5
    Sleep disorder
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    3
    Learning disorder
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Investigations
    Cardiac murmur
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Gamma-Glutamyltransferase increased
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Hepatic enzyme abnormal
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Electrocardiogram repolarisation abnormality
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Lymphocyte morphology abnormal
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Monocyte count decreased
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Burns second degree
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Fall
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Contusion
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Head injury
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Limb injury
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Mouth injury
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Procedural pain
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Sunburn
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Congenital, familial and genetic disorders
    Hip dysplasia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Cardiomyopathy
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Aortic valve incompetence
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Right ventricular hypertrophy
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Left ventricular hypertrophy
         subjects affected / exposed
    4 / 28 (14.29%)
         occurrences all number
    4
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Sinus bradycardia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Hypoaesthesia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Somnolence
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Splenomegaly
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Conductive deafness
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Cerumen impaction
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Deafness
         subjects affected / exposed
    4 / 28 (14.29%)
         occurrences all number
    4
    Ear pain
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Hearing impaired
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Otorrhoea
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Hypoacusis
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Hypermetropia
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Anal fissure
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Constipation
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    3
    Dental caries
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    7 / 28 (25.00%)
         occurrences all number
    35
    Faeces hard
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Gingivitis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Pruritus ani
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Umbilical hernia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    10 / 28 (35.71%)
         occurrences all number
    12
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Dermatitis atopic
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Dermatitis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Dermatitis diaper
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    3
    Eczema
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Heat rash
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    4
    Erythema
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Intertrigo
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Palmar-Plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    6 / 28 (21.43%)
         occurrences all number
    11
    Petechiae
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Rash generalised
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Rash maculo-papular
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Rash papular
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Skin hypopigmentation
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Skin lesion
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    4
    Urticaria papular
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Renal and urinary disorders
    Enuresis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Lordosis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Muscle contracture
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Arthralgia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Body tinea
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Bronchitis
         subjects affected / exposed
    4 / 28 (14.29%)
         occurrences all number
    4
    Catheter site infection
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Bronchopneumonia
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    4
    Candidiasis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Gastroenteritis viral
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Ear infection
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Herpes virus infection
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Gastrointestinal infection
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Gastroenteritis
         subjects affected / exposed
    6 / 28 (21.43%)
         occurrences all number
    7
    Herpes zoster
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Laryngitis
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Lice infestation
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Otitis externa
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    5
    Oral candidiasis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    7 / 28 (25.00%)
         occurrences all number
    18
    Otitis media acute
         subjects affected / exposed
    7 / 28 (25.00%)
         occurrences all number
    10
    Otitis media
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    3
    Otitis media chronic
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Rash pustular
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    11 / 28 (39.29%)
         occurrences all number
    20
    Pneumonia
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    3
    Respiratory tract infection
         subjects affected / exposed
    12 / 28 (42.86%)
         occurrences all number
    36
    Tinea versicolour
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    5 / 28 (17.86%)
         occurrences all number
    6
    Tonsillitis bacterial
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 28 (64.29%)
         occurrences all number
    42
    Tonsillitis
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    6 / 28 (21.43%)
         occurrences all number
    13
    Viral diarrhoea
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Viral pharyngitis
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Varicella
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    9 / 28 (32.14%)
         occurrences all number
    17
    Viral infection
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    4
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Hypercalcaemia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Obesity
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1

    More information

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    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
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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