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    Clinical Trial Results:
    A Phase 3 Randomized, Double Blind, Placebo Controlled Study to Determine the Safety and Efficacy of Romiplostim in Thrombocytopenic Pediatric Subjects with Immune Thrombocytopenia (ITP)

    Summary
    EudraCT number
    2010-018426-39
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    19 Feb 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Jul 2016
    First version publication date
    03 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20080279
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01444417
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Information-Clinical, Amgen (EUROPE) GmbH, MedinfoInternational@amgen.com
    Scientific contact
    IHQ Medical Information-Clinical, Amgen (EUROPE) GmbH, MedinfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000653-PIP01-09
    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
    19 Feb 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the efficacy of romiplostim in the treatment of thrombocytopenia in pediatric subjects with immune thrombocytopenia (ITP) as measured by durable platelet response.
    Protection of trial subjects
    This study was conducted in accordance with the United States Food and Drug Administration (FDA) and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Jan 2012
    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 States: 49
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Canada: 7
    Worldwide total number of subjects
    62
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    39
    Adolescents (12-17 years)
    23
    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
    This study was conducted at 27 centers in the United States, Canada, and Australia.

    Pre-assignment
    Screening details
    Subjects who met eligibility criteria were enrolled and stratified by the following 3 age categories: ≥ 1 to < 6 years; 6 to < 12 years; and 12 to < 18 years.

    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
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received weekly subcutaneous placebo for 24 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo administered once a week by subcutaneous injection

    Arm title
    Romiplostim
    Arm description
    Participants received once weekly subcutaneous romiplostim for 24 weeks at a starting dose of 1 µg/kg; weekly dose increases continued in increments of 1 µg/kg/week to a maximum dose of 10 µg/kg in an attempt to reach a target platelet count of ≥ 50 x 10^9/L.
    Arm type
    Experimental

    Investigational medicinal product name
    Romiplostim
    Investigational medicinal product code
    AMG 531
    Other name
    Nplate
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered weekly as a subcutaneous injection.

    Number of subjects in period 1
    Placebo Romiplostim
    Started
    20
    42
    Received Treatment
    19
    42
    Completed
    18
    41
    Not completed
    2
    1
         Ineligibility determined
    -
    1
         Consent withdrawn by subject
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received weekly subcutaneous placebo for 24 weeks.

    Reporting group title
    Romiplostim
    Reporting group description
    Participants received once weekly subcutaneous romiplostim for 24 weeks at a starting dose of 1 µg/kg; weekly dose increases continued in increments of 1 µg/kg/week to a maximum dose of 10 µg/kg in an attempt to reach a target platelet count of ≥ 50 x 10^9/L.

    Reporting group values
    Placebo Romiplostim Total
    Number of subjects
    20 42 62
    Age categorical
    Units: Subjects
        ≥ 1 - < 6 years
    4 8 12
        ≥ 6 - < 12 years
    9 18 27
        ≥ 12 - < 18 years
    7 16 23
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    9.4 ± 4.7 9.7 ± 4.1 -
    Gender categorical
    Units: Subjects
        Female
    11 24 35
        Male
    9 18 27
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    2 3 5
        Black or African American
    2 6 8
        Multiple
    0 1 1
        Native Hawaiian or Other Pacific Islander
    0 1 1
        Other
    1 5 6
        White
    15 26 41
    Platelets
    Units: 10^9/L
        arithmetic mean (standard deviation)
    19.9 ± 19.3 17.5 ± 10.7 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received weekly subcutaneous placebo for 24 weeks.

    Reporting group title
    Romiplostim
    Reporting group description
    Participants received once weekly subcutaneous romiplostim for 24 weeks at a starting dose of 1 µg/kg; weekly dose increases continued in increments of 1 µg/kg/week to a maximum dose of 10 µg/kg in an attempt to reach a target platelet count of ≥ 50 x 10^9/L.

    Primary: Percentage of Participants with a Durable Platelet Response

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    End point title
    Percentage of Participants with a Durable Platelet Response
    End point description
    A participant with durable platelet response was defined as achieving at least 6 weekly platelet counts of ≥ 50 x 10^9/L during the last 8 weeks of treatment (platelet counts obtained from week 18 to week 25). If a platelet count from a participant was not available (missing) in a certain week, that week was imputed as non-response for that participant. Platelet counts were not deemed as a positive response for 4 weeks after the administration of rescue medication.
    End point type
    Primary
    End point timeframe
    Week 18 to week 25
    End point values
    Placebo Romiplostim
    Number of subjects analysed
    20 [1]
    42 [2]
    Units: percentage of participants
        number (confidence interval 95%)
    10 (1.2 to 31.7)
    52.4 (36.4 to 68)
    Notes
    [1] - Efficacy analysis set includes all randomized subjects
    [2] - Efficacy analysis set includes all randomized subjects
    Statistical analysis title
    Primary Analysis
    Statistical analysis description
    The incidence of durable platelet response was compared by the Cochran-Mantel-Haenszel test stratified by the baseline age group. The Mantel-Haenszel common odds ratio (romiplostim vs placebo) was estimated along with its 95% confidence interval.
    Comparison groups
    Placebo v Romiplostim
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0018 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    9.0497
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.896
         upper limit
    43.199
    Notes
    [3] - p-value from Cochran-Mantel-Haenszel test stratified by baseline age group.

    Secondary: Percentage of Participants with an Overall Platelet Response

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    End point title
    Percentage of Participants with an Overall Platelet Response
    End point description
    Overall platelet response is defined as either a durable platelet response or transient platelet response. Durable platelet response was defined as weekly platelet count ≥ 50 x 10^9/L for 6 or more times for Weeks 18-25 measurements. Subjects may not have a weekly response within 4 weeks after receiving any rescue medication. Transient platelet response was defined as weekly platelet count ≥ 50 x 10^9/L for 4 or more times during Weeks 2-25 measurements but without durable platelet response. Subjects may not have a weekly response within 4 weeks after receiving any rescue medications.
    End point type
    Secondary
    End point timeframe
    Week 2 to week 25
    End point values
    Placebo Romiplostim
    Number of subjects analysed
    20
    42
    Units: percentage of participants
        number (confidence interval 95%)
    20 (5.7 to 43.7)
    71.4 (55.4 to 84.3)
    Statistical analysis title
    Primary Analysis
    Statistical analysis description
    The incidence of overall platelet response was compared by the Cochran-Mantel-Haenszel test stratified by the baseline age group. The Mantel-Haenszel common odds ratio (romiplostim vs placebo) was estimated along with its 95% confidence interval.
    Comparison groups
    Placebo v Romiplostim
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    9.0443
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.535
         upper limit
    32.265
    Notes
    [4] - p-value from Cochran-Mantel-Haenszel test stratified by baseline age group.

    Secondary: Number of Weeks with Platelet Response

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    End point title
    Number of Weeks with Platelet Response
    End point description
    Number of weeks with platelet counts ≥ 50 x 10^9/L during Weeks 2-25 measurements. Subjects may not have a weekly response within 4 weeks after receiving any rescue medications.
    End point type
    Secondary
    End point timeframe
    Week 2 to Week 25
    End point values
    Placebo Romiplostim
    Number of subjects analysed
    20
    42
    Units: weeks
        median (full range (min-max))
    1 (0 to 22)
    12 (0 to 24)
    Statistical analysis title
    Primary Analysis
    Comparison groups
    Placebo v Romiplostim
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004 [5]
    Method
    ANOVA
    Confidence interval
    Notes
    [5] - p-value from Analysis of Variance with main effects (treatment and age group) model after testing for non-significant interaction (p-value ≥ 0.10).

    Secondary: Percentage of Participants who Received Rescue Medication During the Treatment Period

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    End point title
    Percentage of Participants who Received Rescue Medication During the Treatment Period
    End point description
    Rescue medication is any medication (other than excluded medications) that is intended to increase platelet counts or prevent bleeding.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Placebo Romiplostim
    Number of subjects analysed
    20
    42
    Units: percentage of participants
        number (confidence interval 95%)
    45 (23.1 to 68.5)
    40.5 (25.6 to 56.7)
    Statistical analysis title
    Primary Analysis
    Statistical analysis description
    The incidence of rescue medication used was compared by the Cochran-Mantel-Haenszel test stratified by the baseline age group. The Mantel-Haenszel common odds ratio (romiplostim vs placebo)was estimated along with its 95% confidence interval.
    Comparison groups
    Placebo v Romiplostim
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7103 [6]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.813
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.277
         upper limit
    2.391
    Notes
    [6] - p-value from Cochran-Mantel-Haenszel test stratified by baseline age group

    Secondary: Number of Composite Bleeding Episodes

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    End point title
    Number of Composite Bleeding Episodes
    End point description
    A composite bleeding episode was defined as clinically significant bleeding events or the use of a rescue medication to prevent a clinical significant bleeding event during weeks 2 through 25 of the treatment period. A clinically significant bleeding event was defined as a Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 grade ≥ 2 bleeding event.
    End point type
    Secondary
    End point timeframe
    25 weeks
    End point values
    Placebo Romiplostim
    Number of subjects analysed
    20
    42
    Units: composite bleeding episodes
        arithmetic mean (standard deviation)
    4 ± 6.9
    1.9 ± 4.2
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events

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    End point title
    Number of Participants with Adverse Events
    End point description
    A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: • fatal, • life threatening (places the subject at immediate risk of death), • requires in-patient hospitalization or prolongation of existing hospitalization, • results in persistent or significant disability/incapacity, • congenital anomaly/birth defect, and/or • other significant medical hazard. Adverse events were graded for severity according to the CTCAE version 3.0 grading scale, where Grade 3 = moderate, Grade 4 = life-threatening and Grade 5 = fatal. Treatment-related adverse events (TRAEs) were those assessed by the investigator as possibly related to study drug. This relationship was determined by a “yes” or “no” response to the question: “Is there a reasonable possibility that the event may have been caused by study drug?”
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug until 4 weeks after last dose; 28 weeks.
    End point values
    Placebo Romiplostim
    Number of subjects analysed
    19
    42
    Units: participants
        Any adverse event
    19
    41
        Serious adverse events
    1
    10
        Leading to discontinuation of study drug
    0
    0
        Leading to discontinuation from study
    0
    0
        Grade 3
    3
    6
        Grade 4
    1
    2
        Grade 5
    0
    0
        Treatment-related adverse events
    5
    11
        Treatment-related serious adverse events
    0
    1
        TRAE leading to discontinuation of study drug
    0
    0
        TRAE leading to discontinuation from study
    0
    0
        TRAE Grade 3
    0
    1
        TRAE Grade 4
    0
    0
        TRAE Grade 5
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug until 4 weeks after last dose; 28 weeks.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received weekly subcutaneous placebo for 24 weeks.

    Reporting group title
    Romiplostim
    Reporting group description
    Participants received once weekly subcutaneous romiplostim for 24 weeks at a starting dose of 1 µg/kg; weekly dose increases continued in increments of 1 µg/kg/week to a maximum dose of 10 µg/kg in an attempt to reach a target platelet count of ≥ 50 x 10^9/L.

    Serious adverse events
    Placebo Romiplostim
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 19 (5.26%)
    10 / 42 (23.81%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytosis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Petit mal epilepsy
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Romiplostim
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 19 (100.00%)
    41 / 42 (97.62%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    2 / 19 (10.53%)
    4 / 42 (9.52%)
         occurrences all number
    5
    4
    Haemorrhage
         subjects affected / exposed
    2 / 19 (10.53%)
    2 / 42 (4.76%)
         occurrences all number
    3
    3
    Pallor
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    5 / 19 (26.32%)
    7 / 42 (16.67%)
         occurrences all number
    13
    10
    Injection site bruising
         subjects affected / exposed
    2 / 19 (10.53%)
    4 / 42 (9.52%)
         occurrences all number
    6
    6
    Chest pain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Nodule
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Injection site pain
         subjects affected / exposed
    1 / 19 (5.26%)
    4 / 42 (9.52%)
         occurrences all number
    1
    4
    Localised oedema
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 19 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    0
    4
    Pyrexia
         subjects affected / exposed
    2 / 19 (10.53%)
    9 / 42 (21.43%)
         occurrences all number
    2
    12
    Pain
         subjects affected / exposed
    1 / 19 (5.26%)
    4 / 42 (9.52%)
         occurrences all number
    1
    7
    Vessel puncture site bruise
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 42 (2.38%)
         occurrences all number
    1
    1
    Depressed mood
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 42 (4.76%)
         occurrences all number
    1
    2
    Mood altered
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Stress
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Menorrhagia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Metrorrhagia
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 42 (4.76%)
         occurrences all number
    2
    4
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    7
    0
    Animal scratch
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Arthropod bite
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Burns second degree
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Head injury
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    Contusion
         subjects affected / exposed
    7 / 19 (36.84%)
    21 / 42 (50.00%)
         occurrences all number
    34
    134
    Lip injury
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 42 (0.00%)
         occurrences all number
    16
    0
    Muscle strain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Laceration
         subjects affected / exposed
    6 / 19 (31.58%)
    2 / 42 (4.76%)
         occurrences all number
    14
    5
    Post procedural haemorrhage
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 42 (2.38%)
         occurrences all number
    2
    1
    Scratch
         subjects affected / exposed
    2 / 19 (10.53%)
    6 / 42 (14.29%)
         occurrences all number
    5
    7
    Skin abrasion
         subjects affected / exposed
    1 / 19 (5.26%)
    4 / 42 (9.52%)
         occurrences all number
    1
    4
    Sunburn
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 42 (2.38%)
         occurrences all number
    2
    1
    Thermal burn
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Wound
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    Tooth fracture
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Wound haemorrhage
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 42 (4.76%)
         occurrences all number
    1
    2
    Investigations
    Platelet count decreased
         subjects affected / exposed
    3 / 19 (15.79%)
    5 / 42 (11.90%)
         occurrences all number
    9
    20
    Weight increased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 19 (5.26%)
    8 / 42 (19.05%)
         occurrences all number
    1
    11
    Epistaxis
         subjects affected / exposed
    10 / 19 (52.63%)
    20 / 42 (47.62%)
         occurrences all number
    19
    60
    Nasal congestion
         subjects affected / exposed
    1 / 19 (5.26%)
    5 / 42 (11.90%)
         occurrences all number
    1
    5
    Nasal inflammation
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 19 (5.26%)
    11 / 42 (26.19%)
         occurrences all number
    1
    13
    Rhinitis allergic
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 42 (4.76%)
         occurrences all number
    1
    2
    Rhinorrhoea
         subjects affected / exposed
    2 / 19 (10.53%)
    7 / 42 (16.67%)
         occurrences all number
    2
    11
    Blood and lymphatic system disorders
    Increased tendency to bruise
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 42 (2.38%)
         occurrences all number
    2
    1
    Anaemia
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 42 (4.76%)
         occurrences all number
    1
    4
    Lymphadenopathy
         subjects affected / exposed
    1 / 19 (5.26%)
    3 / 42 (7.14%)
         occurrences all number
    2
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 19 (15.79%)
    4 / 42 (9.52%)
         occurrences all number
    5
    5
    Headache
         subjects affected / exposed
    11 / 19 (57.89%)
    17 / 42 (40.48%)
         occurrences all number
    34
    59
    Hypoaesthesia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Presyncope
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Tension headache
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Scleral discolouration
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 19 (10.53%)
    2 / 42 (4.76%)
         occurrences all number
    2
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 19 (15.79%)
    4 / 42 (9.52%)
         occurrences all number
    3
    6
    Constipation
         subjects affected / exposed
    1 / 19 (5.26%)
    5 / 42 (11.90%)
         occurrences all number
    1
    6
    Diarrhoea
         subjects affected / exposed
    3 / 19 (15.79%)
    10 / 42 (23.81%)
         occurrences all number
    3
    13
    Abdominal pain upper
         subjects affected / exposed
    1 / 19 (5.26%)
    5 / 42 (11.90%)
         occurrences all number
    1
    6
    Dyspepsia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Faeces discoloured
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Loose tooth
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Lip haemorrhage
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 42 (4.76%)
         occurrences all number
    1
    2
    Gingival bleeding
         subjects affected / exposed
    4 / 19 (21.05%)
    8 / 42 (19.05%)
         occurrences all number
    6
    10
    Mouth haemorrhage
         subjects affected / exposed
    4 / 19 (21.05%)
    11 / 42 (26.19%)
         occurrences all number
    5
    18
    Mouth ulceration
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    7 / 19 (36.84%)
    8 / 42 (19.05%)
         occurrences all number
    10
    9
    Oral disorder
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 42 (2.38%)
         occurrences all number
    1
    1
    Stomatitis
         subjects affected / exposed
    1 / 19 (5.26%)
    3 / 42 (7.14%)
         occurrences all number
    1
    5
    Tooth socket haemorrhage
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 42 (2.38%)
         occurrences all number
    3
    1
    Vomiting
         subjects affected / exposed
    4 / 19 (21.05%)
    11 / 42 (26.19%)
         occurrences all number
    5
    13
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 19 (5.26%)
    3 / 42 (7.14%)
         occurrences all number
    2
    3
    Proteinuria
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 42 (4.76%)
         occurrences all number
    1
    2
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 19 (10.53%)
    4 / 42 (9.52%)
         occurrences all number
    3
    5
    Dry skin
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 42 (4.76%)
         occurrences all number
    1
    2
    Ecchymosis
         subjects affected / exposed
    2 / 19 (10.53%)
    4 / 42 (9.52%)
         occurrences all number
    2
    5
    Petechiae
         subjects affected / exposed
    6 / 19 (31.58%)
    10 / 42 (23.81%)
         occurrences all number
    11
    62
    Pruritus
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Purpura
         subjects affected / exposed
    0 / 19 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    0
    4
    Rash
         subjects affected / exposed
    2 / 19 (10.53%)
    6 / 42 (14.29%)
         occurrences all number
    3
    8
    Rash vesicular
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Scab
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Skin lesion
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 42 (2.38%)
         occurrences all number
    1
    1
    Skin mass
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 42 (0.00%)
         occurrences all number
    3
    0
    Urticaria
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 19 (15.79%)
    1 / 42 (2.38%)
         occurrences all number
    3
    1
    Bone pain
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    Back pain
         subjects affected / exposed
    2 / 19 (10.53%)
    4 / 42 (9.52%)
         occurrences all number
    3
    4
    Joint range of motion decreased
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Limb discomfort
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 19 (5.26%)
    3 / 42 (7.14%)
         occurrences all number
    1
    3
    Pain in extremity
         subjects affected / exposed
    3 / 19 (15.79%)
    5 / 42 (11.90%)
         occurrences all number
    6
    7
    Temporomandibular joint syndrome
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 19 (5.26%)
    3 / 42 (7.14%)
         occurrences all number
    1
    4
    Polydipsia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 42 (2.38%)
         occurrences all number
    1
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    Oral herpes
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 42 (2.38%)
         occurrences all number
    1
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    Nasopharyngitis
         subjects affected / exposed
    3 / 19 (15.79%)
    2 / 42 (4.76%)
         occurrences all number
    4
    2
    Pneumonia
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    Sinusitis bacterial
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 42 (2.38%)
         occurrences all number
    2
    1
    Tooth abscess
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 19 (26.32%)
    16 / 42 (38.10%)
         occurrences all number
    7
    21
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 19 (5.26%)
    3 / 42 (7.14%)
         occurrences all number
    1
    3
    Viral infection
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 42 (2.38%)
         occurrences all number
    1
    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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