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    Clinical Trial Results:
    A Prospective, Phase IV, Open-Label, Multi-Center Study Evaluating Changes in Bone Marrow Morphology in Adult Subjects Receiving Romiplostim for the Treatment of Thrombocytopenia Associated with Immune (Idiopathic) Thrombocytopenia Purpura (ITP)

    Summary
    EudraCT number
    2008-004347-10
    Trial protocol
    AT   CZ   DE   PL   BE   ES   HU   SE   EE   IT   LT   SI   BG  
    Global end of trial date
    09 Jan 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Jun 2016
    First version publication date
    30 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20080009
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00907478
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Amgen Inc
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the incidence of collagen fibrosis as evidenced by trichrome staining at Year 1, Year 2, or Year 3 after initial exposure of romiplostim.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations and guidelines, and Food and Drug Administration (FDA) regulations. 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
    11 Aug 2009
    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
    Poland: 29
    Country: Number of subjects enrolled
    Slovenia: 3
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Czech Republic: 12
    Country: Number of subjects enrolled
    Estonia: 3
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Lithuania: 11
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Russian Federation: 15
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    169
    EEA total number of subjects
    101
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    130
    From 65 to 84 years
    38
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Eligible patients were adults diagnosed with immune (idiopathic) thrombocytopenic purpura (ITP) with a platelet count < 50 x 10^9/L. The first patient enrolled 11 August 2009 and the last patient was enrolled 11 November 2010. Participants were enrolled at 60 study centers in Australia, Europe, and North America.

    Pre-assignment
    Screening details
    204 patients were screened, 35 were considered screen failures. Participants were enrolled sequentially into the following cohorts: • Bone marrow biopsy at Baseline and Year 1 • Bone marrow biopsy at Baseline and Year 2 • Bone marrow biopsy at Baseline and Year 3.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1
    Arm description
    Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 1.
    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
    Romiplostim administered by subcutaneous injection. The starting dose was 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 title
    Cohort 2
    Arm description
    Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 2.
    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
    Romiplostim administered by subcutaneous injection. The starting dose was 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 title
    Cohort 3
    Arm description
    Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 3.
    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
    Romiplostim administered by subcutaneous injection. The starting dose was 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.

    Number of subjects in period 1
    Cohort 1 Cohort 2 Cohort 3
    Started
    50
    50
    69
    Completed
    23
    33
    47
    Not completed
    27
    17
    22
         Consent withdrawn by subject
    8
    9
    6
         Physician decision
    2
    -
    3
         'Ineligibility determined '
    -
    -
    1
         Death
    4
    2
    1
         Other
    3
    -
    1
         Pregnancy
    -
    1
    1
         Adverse event
    3
    1
    2
         Lost to follow-up
    1
    -
    -
         Requirement for alternative therapy
    1
    2
    3
         Protocol-specified criteria
    5
    2
    3
         Noncompliance
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 1.

    Reporting group title
    Cohort 2
    Reporting group description
    Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 2.

    Reporting group title
    Cohort 3
    Reporting group description
    Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 3.

    Reporting group values
    Cohort 1 Cohort 2 Cohort 3 Total
    Number of subjects
    50 50 69 169
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.5 ± 17.1 48.6 ± 16.5 46.6 ± 16.3 -
    Gender categorical
    Units: Subjects
        Female
    27 38 49 114
        Male
    23 12 20 55
    Race/Ethnicity
    Units: Subjects
        White or Caucasian
    48 47 59 154
        Black or African American
    0 0 1 1
        Hispanic or Latino
    1 3 7 11
        Asian
    1 0 1 2
        Other
    0 0 1 1
    Number of Prior ITP Therapies
    Units: Subjects
        None
    0 0 0 0
        One
    16 16 29 61
        Two
    11 15 20 46
        Three
    8 9 10 27
        Four or more
    15 10 10 35
    Had Splenectomy
    Units: Subjects
        No
    28 35 46 109
        Yes
    22 15 23 60
    Any Prior History of Bone Marrow Abnormalities
    Units: Subjects
        No
    48 47 64 159
        Yes
    2 3 5 10
    Time Since ITP Diagnosis
    Units: years
        arithmetic mean (standard deviation)
    9.94 ± 10.29 10.5 ± 11.87 5.36 ± 6.41 -

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 1.

    Reporting group title
    Cohort 2
    Reporting group description
    Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 2.

    Reporting group title
    Cohort 3
    Reporting group description
    Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 3.

    Subject analysis set title
    Overall
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants received once weekly romiplostim for 3 years.

    Primary: Percentage of Subjects With Collagen Fibrosis

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    End point title
    Percentage of Subjects With Collagen Fibrosis [1]
    End point description
    The percentage of subjects who developed collagen fibrosis as evidenced by trichrome staining. Bone marrow biopsy samples were assessed using the modified Bauermeister grading scale by a central laboratory.
    End point type
    Primary
    End point timeframe
    At Years 1, 2 or 3 after initial exposure of romiplostim
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing were performed on any endpoints in this open label study.
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    35 [2]
    39 [3]
    58 [4]
    Units: percentage of subject
        number (confidence interval 95%)
    0 (0 to 10)
    0 (0 to 9)
    3.4 (0.4 to 11.9)
    Notes
    [2] - Subjects with evaluable trichrome stain results
    [3] - Subjects with evaluable trichrome stain results
    [4] - Subjects with evaluable trichrome stain results
    No statistical analyses for this end point

    Secondary: Number of Subjects With Collagen Fibrosis 12 Weeks After Romiplostim Discontinuation in Subjects Who Developed Collagen Fibrosis at Years 1, 2, or 3

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    End point title
    Number of Subjects With Collagen Fibrosis 12 Weeks After Romiplostim Discontinuation in Subjects Who Developed Collagen Fibrosis at Years 1, 2, or 3
    End point description
    The number of subjects with collagen fibrosis as evidenced by trichrome staining 12 weeks after romiplostim discontinuation in subjects who developed collagen fibrosis at Years 1, 2, or 3 after initial exposure of romiplostim, assessed by the central laboratory using the modified Bauermeister grading scale.
    End point type
    Secondary
    End point timeframe
    12 weeks after romiplostim discontinuation
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    0 [5]
    0 [6]
    1 [7]
    Units: subjects
    0
    Notes
    [5] - Sujects with collagen fibrosis at Year 1
    [6] - Subjects with collagen fibrosis at Year 2
    [7] - Subjects with collagen fibrosis at Year 3 and with available trichome staining results
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Developed an Increased Modified Bauermeister Grade

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    End point title
    Percentage of Subjects Who Developed an Increased Modified Bauermeister Grade
    End point description
    Increased modified Bauermeister grade refers to an increase by ≥ 2 severity grades or an increase to grade 4 (ie, grade 0 to 2-4, grade 1 to 3-4, grade 2 to 4, or grade 3 to 4 over baseline). The modified Bauermeister scale provides a means of assessing the development of increased reticulin and collagen in bone marrow according to the following: Grade 0: No reticulin fibers demonstrable; Grade 1: Occasional fine individual fibers and foci of a fine fiber network; Grade 2: Fine fiber network throughout most of the section; no coarse fibers; Grade 3: Diffuse fiber network with scattered thick coarse fibers but no mature collagen (negative to trichrome staining); Grade 4: Diffuse, often course fiber network with areas of collagenization (positive trichrome staining).
    End point type
    Secondary
    End point timeframe
    At Year 1, Year 2, or Year 3 post romiplostim exposure
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    34 [8]
    39 [9]
    58 [10]
    Units: percentage of subject
        number (confidence interval 95%)
    0 (0 to 10.3)
    5.1 (0.6 to 17.3)
    12.1 (5 to 23.3)
    Notes
    [8] - Subjects with evaluable reticulin silver stain results
    [9] - Subjects with evaluable reticulin silver stain results
    [10] - Subjects with evaluable reticulin silver stain results
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinically Relevant Changes in Total Cardiac Output Corrected (QTc) Intervals

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    End point title
    Percentage of Subjects With Clinically Relevant Changes in Total Cardiac Output Corrected (QTc) Intervals
    End point description
    A clinically relevant change in QTc (Fridericia) interval is defined as an absolute QTc interval >500 ms or a QTc Interval increase from Baseline >60 ms post romiplostim exposure. 12-lead electrocardiograms (ECG) were performed in triplicate at Baseline, Week 3 and Week 12; the average of of the 3 values at each assessment was used.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 3 and Week 12
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    50 [11]
    50 [12]
    69 [13]
    Units: Percentage of subjects
        number (confidence interval 95%)
    0 (0 to 7.1)
    0 (0 to 7.1)
    0 (0 to 5.2)
    Notes
    [11] - All subjects who received at least one dose of romiplostim.
    [12] - All subjects who received at least one dose of romiplostim.
    [13] - All subjects who received at least one dose of romiplostim.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Improvement of Reticulin to a Grade of ≤ 2 for Subjects Who Developed Grade 3 Reticulin

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    End point title
    Number of Subjects With Improvement of Reticulin to a Grade of ≤ 2 for Subjects Who Developed Grade 3 Reticulin
    End point description
    The number of subjects who had any improvement of reticulin to a grade of ≤ 2 for subjects who developed grade 3 reticulin after initial exposure to romiplostim as measured by the modified Bauermeister grading scale. The modified Bauermeister scale provides a means of assessing the development of increased reticulin and collagen in bone marrow according to the following: Grade 0: No reticulin fibers demonstrable; Grade 1: Occasional fine individual fibers and foci of a fine fiber network; Grade 2: Fine fiber network throughout most of the section; no coarse fibers; Grade 3: Diffuse fiber network with scattered thick coarse fibers but no mature collagen (negative to trichrome staining); Grade 4: Diffuse, often course fiber network with areas of collagenization (positive trichrome staining). Two subjects with grade 3 reticulin did not have a bone marrow biopsy performed 12 weeks after romiploastim discontinuation.
    End point type
    Secondary
    End point timeframe
    12 weeks after romiplostim discontinuation
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    0 [14]
    0 [15]
    3 [16]
    Units: subjects
    3
    Notes
    [14] - Subjects with Grade 3 reticulin at Year 1 and who had a follow-up bone marrow biopsy
    [15] - Subjects with Grade 3 reticulin at Year 2 and who had a follow-up bone marrow biopsy
    [16] - Subjects with Grade 3 reticulin at Year 3 and who had a follow-up bone marrow biopsy
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With CTCAE Grade ≥ 2 Shift in Anemia or Neutropenia

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    End point title
    Percentage of Subjects With CTCAE Grade ≥ 2 Shift in Anemia or Neutropenia
    End point description
    Anemia was identified by laboratory values with hemoglobin < the lower limit of normal (LLN) or the Medical Dictionary for Regulatory Activities (MedDRA) terms prespecified by the sponsor. Neutropenia was identified by laboratory values with absolute neutrophil count <1.8x10^9/L or the MedDRA terms pre-specified by the sponsor. Severity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, based on the following: Grade 1: Mild AE; Grade 2: Moderate AE; Grade 3: Severe AE; Grade 4: Life-threatening or disabling AE; Grade 5: Death related to AE.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug until 4 weeks after treatment discontinuation or 12 weeks after treatment discontinuation for patients who developed collagen fibrosis or a change to grade 3 reticulin; the overall median treatment duration was 154 weeks.
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    50 [17]
    50 [18]
    69 [19]
    Units: percentage of subjects
    number (confidence interval 95%)
        CTCAE grade ≥2 shift in anemia
    6 (1.3 to 16.5)
    4 (0.5 to 13.7)
    8.7 (3.3 to 18)
        CTCAE grade ≥2 shift in neutropenia
    8 (2.2 to 19.2)
    6 (1.3 to 16.5)
    13 (6.1 to 23.3)
    Notes
    [17] - Subjects who received at least one dose of romiplostim
    [18] - Subjects who received at least one dose of romiplostim
    [19] - Subjects who received at least one dose of romiplostim
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events (AEs)

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    End point title
    Number of Subjects With Adverse Events (AEs)
    End point description
    An AE was defined as any untoward medical occurrence in a participant that did not necessarily have a causal relationship with this treatment, or any such occurrence or worsening of a pre-existing medical condition from the first dose of investigational product through the last study visit. A serious adverse event is defined as an AE that is fatal or life threatening, requires or prolongs hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or other significant medical hazard. The relationship of each AE to the study drug was assessed by the investigator. The severity of each AE was graded using using CTCAE 3.0; For any AEs not listed in CTCAE, the Amgen Standard Severity Scoring System was used: 1: Mild- Aware of sign or symptom, but easily tolerated; 2 Moderate- Discomfort enough to cause interference with usual activity; 3: Severe- Incapacitating with inability to work or do usual activity; 4: Life-threatening; 5: Fatal.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug until 4 weeks after treatment discontinuation or 12 weeks after treatment discontinuation for patients who developed collagen fibrosis or a change to grade 3 reticulin; the overall median treatment duration was 154 weeks.
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    50 [20]
    50 [21]
    69 [22]
    Units: subjects
        All adverse events
    46
    45
    67
        Grade ≥ 2
    39
    39
    59
        Grade ≥ 3
    25
    21
    38
        Grade ≥ 4
    13
    8
    16
        Serious adverse events
    16
    12
    28
        Leading to discontinuation of study drug
    6
    5
    4
        Leading to discontinuation from study
    6
    2
    3
        Fatal adverse events
    4
    2
    1
        Treatment-related adverse events
    14
    22
    24
        Treatment-related grade ≥ 2
    8
    14
    10
        Treatment-related grade ≥ 3
    2
    7
    3
        Treatment-related grade ≥ 4
    0
    1
    0
        Treatment-related serious adverse events
    1
    2
    3
        Treatment-related -> discontinuation of study drug
    1
    1
    2
        Treatment-related -> discontinuation from study
    1
    0
    2
        Treatment-related fatal adverse events
    0
    0
    0
    Notes
    [20] - Subjects who received at least one dose of romiplostim
    [21] - Subjects who received at least one dose of romiplostim
    [22] - Subjects who received at least one dose of romiplostim
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Developed Antibodies or Neutralizing Antibodies to Romiplostim or to Endogenous Thrombopoietin

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    End point title
    Number of Subjects Who Developed Antibodies or Neutralizing Antibodies to Romiplostim or to Endogenous Thrombopoietin
    End point description
    Two validated assays were used to test for antibodies to romiplostim, the thrombopoietin-mimetic peptide component of romiplostim (TMP) and to endogenous thrombopoietin (TPO). The first was an immunoassay to confirm the presence of antibodies. The second was a cell-based bioassay to detect neutralizing or inhibitory effects in vitro. If a sample was positive in both assays, a participant was defined as positive for neutralizing antibodies. Persistent antibodies were those positive at the last timepoint tested and transient are defined as positive post-dose but negative at the last time point tested.
    End point type
    Secondary
    End point timeframe
    Every 24 weeks and at the end of study visit (4 weeks or 12 weeks after study drug discontinuation).
    End point values
    Overall
    Number of subjects analysed
    69 [23]
    Units: subjects
        Antibodies to romiplostim
    7
        Persistent antibodies to romiplostim
    4
        Transient antibodies to romiplostim
    3
        Antibodies to TMP
    4
        Persistent antibodies to TMP
    1
        Transient antibodies to TMP
    3
        Antibodies to TPO
    6
        Persistent antibodies to TPO
    2
        Transient antibodies to TPO
    4
        Neutralizing antibodies to romiplostim
    1
        Neutralizing antibodies to TPO
    0
    Notes
    [23] - All subjects who received at least one dose of romiplostim
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    3 years
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 1.

    Reporting group title
    Cohort 2
    Reporting group description
    Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 2.

    Reporting group title
    Cohort 3
    Reporting group description
    Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 3.

    Reporting group title
    Overall
    Reporting group description
    Participants received once weekly romiplostim for 3 years.

    Serious adverse events
    Cohort 1 Cohort 2 Cohort 3 Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 50 (32.00%)
    12 / 50 (24.00%)
    28 / 69 (40.58%)
    56 / 169 (33.14%)
         number of deaths (all causes)
    4
    2
    1
    7
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    2 / 69 (2.90%)
    2 / 169 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Surgical and medical procedures
    Knee operation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth extraction
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic ovarian cyst
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    0 / 69 (0.00%)
    2 / 169 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Pulmonary thrombosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Investigations
    Clostridium test positive
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    2 / 69 (2.90%)
    2 / 169 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    2 / 169 (1.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Complicated migraine
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    1 / 69 (1.45%)
    2 / 169 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sensory disturbance
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal claudication
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    2 / 69 (2.90%)
    3 / 169 (1.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic diathesis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Idiopathic thrombocytopenic purpura
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    2 / 69 (2.90%)
    3 / 169 (1.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 50 (0.00%)
    4 / 69 (5.80%)
    6 / 169 (3.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 8
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyphaema
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute abdomen
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gingival disorder
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    2 / 69 (2.90%)
    2 / 169 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lichenoid keratosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin disorder
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Anuria
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus urethral
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    1 / 69 (1.45%)
    2 / 169 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Exostosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    2 / 69 (2.90%)
    2 / 169 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess jaw
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal sepsis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Lobar pneumonia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    2 / 169 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    1 / 69 (1.45%)
    2 / 169 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    2 / 69 (2.90%)
    2 / 169 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 50 (2.00%)
    0 / 69 (0.00%)
    3 / 169 (1.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 69 (0.00%)
    1 / 169 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort 1 Cohort 2 Cohort 3 Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 50 (90.00%)
    43 / 50 (86.00%)
    66 / 69 (95.65%)
    154 / 169 (91.12%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 50 (6.00%)
    10 / 69 (14.49%)
    15 / 169 (8.88%)
         occurrences all number
    2
    7
    23
    32
    Hypertension
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 50 (8.00%)
    5 / 69 (7.25%)
    9 / 169 (5.33%)
         occurrences all number
    0
    4
    6
    10
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    8 / 69 (11.59%)
    9 / 169 (5.33%)
         occurrences all number
    1
    0
    10
    11
    Fatigue
         subjects affected / exposed
    6 / 50 (12.00%)
    8 / 50 (16.00%)
    7 / 69 (10.14%)
    21 / 169 (12.43%)
         occurrences all number
    9
    10
    8
    27
    Influenza like illness
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 50 (6.00%)
    3 / 69 (4.35%)
    6 / 169 (3.55%)
         occurrences all number
    0
    7
    5
    12
    Local swelling
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 50 (10.00%)
    3 / 69 (4.35%)
    13 / 169 (7.69%)
         occurrences all number
    6
    8
    4
    18
    Malaise
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 50 (6.00%)
    1 / 69 (1.45%)
    4 / 169 (2.37%)
         occurrences all number
    0
    3
    1
    4
    Oedema peripheral
         subjects affected / exposed
    4 / 50 (8.00%)
    3 / 50 (6.00%)
    4 / 69 (5.80%)
    11 / 169 (6.51%)
         occurrences all number
    7
    5
    5
    17
    Pain
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    5 / 69 (7.25%)
    7 / 169 (4.14%)
         occurrences all number
    0
    2
    5
    7
    Pyrexia
         subjects affected / exposed
    6 / 50 (12.00%)
    4 / 50 (8.00%)
    10 / 69 (14.49%)
    20 / 169 (11.83%)
         occurrences all number
    7
    4
    19
    30
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 50 (8.00%)
    7 / 50 (14.00%)
    13 / 69 (18.84%)
    24 / 169 (14.20%)
         occurrences all number
    4
    8
    27
    39
    Dyspnoea
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 50 (0.00%)
    3 / 69 (4.35%)
    7 / 169 (4.14%)
         occurrences all number
    5
    0
    3
    8
    Epistaxis
         subjects affected / exposed
    9 / 50 (18.00%)
    10 / 50 (20.00%)
    18 / 69 (26.09%)
    37 / 169 (21.89%)
         occurrences all number
    9
    20
    38
    67
    Oropharyngeal pain
         subjects affected / exposed
    1 / 50 (2.00%)
    6 / 50 (12.00%)
    10 / 69 (14.49%)
    17 / 169 (10.06%)
         occurrences all number
    1
    11
    14
    26
    Rhinorrhoea
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    5 / 69 (7.25%)
    8 / 169 (4.73%)
         occurrences all number
    2
    3
    5
    10
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 50 (6.00%)
    7 / 50 (14.00%)
    3 / 69 (4.35%)
    13 / 169 (7.69%)
         occurrences all number
    3
    9
    3
    15
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    6 / 50 (12.00%)
    9 / 50 (18.00%)
    19 / 69 (27.54%)
    34 / 169 (20.12%)
         occurrences all number
    10
    16
    42
    68
    Fall
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 50 (4.00%)
    5 / 69 (7.25%)
    9 / 169 (5.33%)
         occurrences all number
    2
    4
    5
    11
    Laceration
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 50 (6.00%)
    5 / 69 (7.25%)
    9 / 169 (5.33%)
         occurrences all number
    1
    4
    8
    13
    Procedural pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    7 / 69 (10.14%)
    7 / 169 (4.14%)
         occurrences all number
    0
    0
    8
    8
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    4 / 69 (5.80%)
    6 / 169 (3.55%)
         occurrences all number
    1
    1
    5
    7
    Tachycardia
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 50 (0.00%)
    1 / 69 (1.45%)
    4 / 169 (2.37%)
         occurrences all number
    3
    0
    1
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 50 (8.00%)
    6 / 50 (12.00%)
    4 / 69 (5.80%)
    14 / 169 (8.28%)
         occurrences all number
    4
    9
    11
    24
    Headache
         subjects affected / exposed
    12 / 50 (24.00%)
    14 / 50 (28.00%)
    25 / 69 (36.23%)
    51 / 169 (30.18%)
         occurrences all number
    17
    39
    62
    118
    Paraesthesia
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    5 / 69 (7.25%)
    8 / 169 (4.73%)
         occurrences all number
    1
    2
    6
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 50 (4.00%)
    4 / 69 (5.80%)
    8 / 169 (4.73%)
         occurrences all number
    2
    4
    5
    11
    Idiopathic thrombocytopenic purpura
         subjects affected / exposed
    8 / 50 (16.00%)
    6 / 50 (12.00%)
    8 / 69 (11.59%)
    22 / 169 (13.02%)
         occurrences all number
    27
    13
    23
    63
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 50 (2.00%)
    4 / 69 (5.80%)
    7 / 169 (4.14%)
         occurrences all number
    2
    1
    4
    7
    Neutrophilia
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 50 (0.00%)
    0 / 69 (0.00%)
    3 / 169 (1.78%)
         occurrences all number
    3
    0
    0
    3
    Thrombocytopenia
         subjects affected / exposed
    8 / 50 (16.00%)
    3 / 50 (6.00%)
    6 / 69 (8.70%)
    17 / 169 (10.06%)
         occurrences all number
    21
    4
    15
    40
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    5 / 69 (7.25%)
    7 / 169 (4.14%)
         occurrences all number
    2
    1
    7
    10
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 50 (4.00%)
    2 / 69 (2.90%)
    7 / 169 (4.14%)
         occurrences all number
    3
    2
    2
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 50 (4.00%)
    8 / 69 (11.59%)
    12 / 169 (7.10%)
         occurrences all number
    2
    2
    12
    16
    Abdominal pain lower
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    4 / 69 (5.80%)
    4 / 169 (2.37%)
         occurrences all number
    0
    0
    4
    4
    Abdominal pain upper
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 50 (6.00%)
    5 / 69 (7.25%)
    10 / 169 (5.92%)
         occurrences all number
    2
    5
    6
    13
    Constipation
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 50 (6.00%)
    5 / 69 (7.25%)
    11 / 169 (6.51%)
         occurrences all number
    3
    3
    7
    13
    Diarrhoea
         subjects affected / exposed
    7 / 50 (14.00%)
    7 / 50 (14.00%)
    18 / 69 (26.09%)
    32 / 169 (18.93%)
         occurrences all number
    10
    14
    35
    59
    Gingival bleeding
         subjects affected / exposed
    3 / 50 (6.00%)
    5 / 50 (10.00%)
    13 / 69 (18.84%)
    21 / 169 (12.43%)
         occurrences all number
    3
    11
    21
    35
    Haemorrhoids
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    4 / 69 (5.80%)
    5 / 169 (2.96%)
         occurrences all number
    0
    3
    4
    7
    Mouth haemorrhage
         subjects affected / exposed
    6 / 50 (12.00%)
    5 / 50 (10.00%)
    2 / 69 (2.90%)
    13 / 169 (7.69%)
         occurrences all number
    12
    8
    3
    23
    Nausea
         subjects affected / exposed
    6 / 50 (12.00%)
    7 / 50 (14.00%)
    11 / 69 (15.94%)
    24 / 169 (14.20%)
         occurrences all number
    6
    10
    21
    37
    Vomiting
         subjects affected / exposed
    5 / 50 (10.00%)
    6 / 50 (12.00%)
    8 / 69 (11.59%)
    19 / 169 (11.24%)
         occurrences all number
    7
    7
    9
    23
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    7 / 69 (10.14%)
    7 / 169 (4.14%)
         occurrences all number
    0
    0
    8
    8
    Ecchymosis
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 50 (6.00%)
    4 / 69 (5.80%)
    9 / 169 (5.33%)
         occurrences all number
    3
    23
    8
    34
    Petechiae
         subjects affected / exposed
    9 / 50 (18.00%)
    11 / 50 (22.00%)
    14 / 69 (20.29%)
    34 / 169 (20.12%)
         occurrences all number
    22
    14
    27
    63
    Pruritus
         subjects affected / exposed
    1 / 50 (2.00%)
    6 / 50 (12.00%)
    8 / 69 (11.59%)
    15 / 169 (8.88%)
         occurrences all number
    1
    8
    16
    25
    Rash
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 50 (8.00%)
    7 / 69 (10.14%)
    14 / 169 (8.28%)
         occurrences all number
    3
    4
    12
    19
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 50 (16.00%)
    10 / 50 (20.00%)
    19 / 69 (27.54%)
    37 / 169 (21.89%)
         occurrences all number
    11
    12
    39
    62
    Back pain
         subjects affected / exposed
    5 / 50 (10.00%)
    8 / 50 (16.00%)
    11 / 69 (15.94%)
    24 / 169 (14.20%)
         occurrences all number
    6
    13
    16
    35
    Bone pain
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 50 (8.00%)
    1 / 69 (1.45%)
    6 / 169 (3.55%)
         occurrences all number
    1
    4
    1
    6
    Musculoskeletal pain
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    5 / 69 (7.25%)
    8 / 169 (4.73%)
         occurrences all number
    1
    3
    6
    10
    Myalgia
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    9 / 69 (13.04%)
    12 / 169 (7.10%)
         occurrences all number
    1
    2
    17
    20
    Neck pain
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 50 (2.00%)
    4 / 69 (5.80%)
    7 / 169 (4.14%)
         occurrences all number
    2
    1
    4
    7
    Pain in extremity
         subjects affected / exposed
    4 / 50 (8.00%)
    5 / 50 (10.00%)
    8 / 69 (11.59%)
    17 / 169 (10.06%)
         occurrences all number
    11
    5
    14
    30
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 50 (6.00%)
    9 / 50 (18.00%)
    12 / 69 (17.39%)
    24 / 169 (14.20%)
         occurrences all number
    5
    10
    16
    31
    Influenza
         subjects affected / exposed
    1 / 50 (2.00%)
    7 / 50 (14.00%)
    8 / 69 (11.59%)
    16 / 169 (9.47%)
         occurrences all number
    1
    16
    24
    41
    Nasopharyngitis
         subjects affected / exposed
    6 / 50 (12.00%)
    21 / 50 (42.00%)
    14 / 69 (20.29%)
    41 / 169 (24.26%)
         occurrences all number
    8
    41
    42
    91
    Pharyngitis
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 50 (8.00%)
    6 / 69 (8.70%)
    11 / 169 (6.51%)
         occurrences all number
    1
    4
    24
    29
    Respiratory tract infection
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 50 (6.00%)
    2 / 69 (2.90%)
    7 / 169 (4.14%)
         occurrences all number
    2
    4
    2
    8
    Sinusitis
         subjects affected / exposed
    3 / 50 (6.00%)
    5 / 50 (10.00%)
    7 / 69 (10.14%)
    15 / 169 (8.88%)
         occurrences all number
    6
    17
    14
    37
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 50 (22.00%)
    7 / 50 (14.00%)
    13 / 69 (18.84%)
    31 / 169 (18.34%)
         occurrences all number
    25
    9
    31
    65
    Urinary tract infection
         subjects affected / exposed
    4 / 50 (8.00%)
    6 / 50 (12.00%)
    6 / 69 (8.70%)
    16 / 169 (9.47%)
         occurrences all number
    4
    7
    11
    22
    Viral infection
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 50 (6.00%)
    7 / 69 (10.14%)
    11 / 169 (6.51%)
         occurrences all number
    4
    3
    9
    16
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 50 (6.00%)
    2 / 69 (2.90%)
    7 / 169 (4.14%)
         occurrences all number
    2
    4
    2
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Sep 2010
    - Added a request for the collection of bone marrow biopsies for subjects that early terminate and have not previously provided a cohort-defined biopsy. - Bone marrow aspirates will no longer be specifically requested per protocol as there are no planned evaluations or analysis for these samples. However, additional bone marrow biopsies and aspirates may be performed if clinically indicated at the discretion of the investigator and/or Amgen. - Clarified frequency of bone marrow panel review

    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
    For support, Contact us.
    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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