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    Clinical Trial Results:
    A Single Arm, Open-label, Long-term Efficacy and Safety Study of Romiplostim in Thrombocytopenic Pediatric Subjects With Immune Thrombocytopenia (ITP)

    Summary
    EudraCT number
    		 2011-005019-96
    Trial protocol
    		 CZ   BE   ES   GB   HU   Outside EU/EEA   PL   FR  
    Global end of trial date
    08 Aug 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    22 Aug 2020
    First version publication date
    22 Feb 2020
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction to AE time frame

    Trial information

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    Trial identification
    Sponsor protocol code
    20101221
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02279173
    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 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)
    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
    08 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives were as follows: - to describe the percentage of time that pediatric subjects with ITP have a platelet response in the first 6 months from the start of treatment with romiplostim - to evaluate the incidence of changes in bone marrow findings at year 1 or year 2 after initial exposure to romiplostim
    Protection of trial subjects
    This study was conducted in accordance with the United States Food and Drug Administration (FDA) and International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. The protocol, informed consent, and all other subject information and/or recruitment materials were submitted to the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) of each study center for approval. The investigator or a designee was to obtain written informed consent from their subjects or legally acceptable representatives after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study and before any protocol-specific screening procedures were conducted or investigational product was administered.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Dec 2014
    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
    South Africa: 8
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 34
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Czech Republic: 11
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Israel: 20
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Russian Federation: 41
    Worldwide total number of subjects
    203
    EEA total number of subjects
    68
    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)
    1
    Children (2-11 years)
    129
    Adolescents (12-17 years)
    73
    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
    		 Children with immune thrombocytopenic purpura (ITP) and platelet counts ≤ 30×10⁹/L or uncontrolled bleeding were enrolled from December 2014 to August 2016 at 66 centers in 16 countries worldwide, including Eastern Europe (44%), Western Europe (25%), and US/Canada (21%).

    Pre-assignment
    Screening details
    		 All participants were assigned to receive weekly romiplostim. A subset of participants enrolled under a protocol supplement in the European Union (EU), Switzerland, and Turkey were enrolled into the following 2 cohorts: • bone marrow biopsy and aspirate at baseline and year 1 • bone marrow biopsy and aspirate at baseline and year 2

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

    Arms
    Arm title
    		 Romiplostim
    Arm description
    		 Participants received romiplostim administered weekly by subcutaneous injection for up to 3 years. The starting dose was 1 µg/kg titrated in 1 µg/kg increments up to a maximum of 10 µg/kg to reach a target platelet count ≥ 50 x 10⁹/L.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Romiplostim
    Investigational medicinal product code
    AMG 531
    Other name
    NPLATE
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Romiplostim subcutaneous weekly injection

    Number of subjects in period 1
    		Romiplostim
    Started
    203
    Received Treatment
    203
    Enrolled Under Protocol Supplement
    79 [1]
    Completed
    109
    Not completed
    94
         Consent withdrawn by subject
    20
         Decision by Sponsor
    4
         Lost to follow-up
    3
         Protocol-specified Criteria
    67
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones present the number of subjects who received treatment and those who enrolled under a protocol supplement.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Romiplostim
    Reporting group description
    		 Participants received romiplostim administered weekly by subcutaneous injection for up to 3 years. The starting dose was 1 µg/kg titrated in 1 µg/kg increments up to a maximum of 10 µg/kg to reach a target platelet count ≥ 50 x 10⁹/L.

    Reporting group values
    		 Romiplostim Total
    Number of subjects
    		 203 203
    Age Categorical
    Units: participants
        ≥ 1 to < 6 years
    		 49 49
        ≥ 6 to < 12 years
    		 81 81
        ≥ 12 to < 18 years
    		 73 73
    Age Continuous
    Units: years
        median (full range (min-max))
    		 10.0 (1 to 17) -
    Sex: Female, Male
    Units: participants
        Female
    		 103 103
        Male
    		 100 100
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 4 4
        Asian
    		 12 12
        Black or African American
    		 11 11
        Multiple
    		 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Other
    		 11 11
        White
    		 164 164
    Splenectomy Done
    Units: Subjects
        Yes
    		 10 10
        No
    		 193 193
    Years Since ITP Diagnosis
    Units: years
        median (full range (min-max))
    		 1.75 (0.5 to 13.8) -
    Age at ITP Diagnosis
    Units: years
        median (full range (min-max))
    		 5.97 (0.6 to 17.3) -
    Platelet Count
    Units: 10⁹ cells/L
        median (full range (min-max))
    		 14.00 (1.5 to 265.0) -
    Number of Prior ITP Treatments
    Units: prior ITP treatments
        median (full range (min-max))
    		 2.0 (1 to 7) -
    Subject analysis sets

    Subject analysis set title
    Cohort 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants enrolled under the protocol supplement in the EU, Switzerland, or Turkey received weekly romiplostim for 3 years and had a bone marrow biopsy at baseline and year 1.

    Subject analysis set title
    Cohort 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants enrolled under the protocol supplement in the EU, Switzerland, or Turkey received weekly romiplostim for 3 years and had a bone marrow biopsy at baseline and year 2.

    Subject analysis sets values
    		 Cohort 1 Cohort 2
    Number of subjects
    30
    49
    Age Categorical
    Units: participants
        ≥ 1 to < 6 years
    7
    14
        ≥ 6 to < 12 years
    13
    13
        ≥ 12 to < 18 years
    10
    22
    Age Continuous
    Units: years
        median (full range (min-max))
    10.5 (2 to 16)
    10.0 (1 to 17)
    Sex: Female, Male
    Units: participants
        Female
    15
    27
        Male
    15
    22
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    0
    0
        Asian
    2
    4
        Black or African American
    0
    1
        Multiple
    0
    0
        Native Hawaiian or Other Pacific Islander
    0
    0
        Other
    2
    0
        White
    26
    44
    Splenectomy Done
    Units: Subjects
        Yes
    1
    2
        No
    29
    47
    Years Since ITP Diagnosis
    Units: years
        median (full range (min-max))
    3.08 (0.6 to 11.0)
    1.14 (0.5 to 11.2)
    Age at ITP Diagnosis
    Units: years
        median (full range (min-max))
    5.38 (0.6 to 16.2)
    7.63 (1.3 to 16.0)
    Platelet Count
    Units: 10⁹ cells/L
        median (full range (min-max))
    Number of Prior ITP Treatments
    Units: prior ITP treatments
        median (full range (min-max))
    2.0 (1 to 5)
    2.0 (1 to 7)

    End points

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    End points reporting groups
    Reporting group title
    Romiplostim
    Reporting group description
    		 Participants received romiplostim administered weekly by subcutaneous injection for up to 3 years. The starting dose was 1 µg/kg titrated in 1 µg/kg increments up to a maximum of 10 µg/kg to reach a target platelet count ≥ 50 x 10⁹/L.

    Subject analysis set title
    Cohort 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants enrolled under the protocol supplement in the EU, Switzerland, or Turkey received weekly romiplostim for 3 years and had a bone marrow biopsy at baseline and year 1.

    Subject analysis set title
    Cohort 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants enrolled under the protocol supplement in the EU, Switzerland, or Turkey received weekly romiplostim for 3 years and had a bone marrow biopsy at baseline and year 2.

    Primary: Percentage of Time with a Platelet Response During the First 6 Months of Treatment

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    End point title
    		 Percentage of Time with a Platelet Response During the First 6 Months of Treatment [1]
    End point description
    Platelet response was defined as a platelet count of ≥ 50 x 10⁹/L with no rescue medication use for ITP in the past 4 weeks. Monthly platelet response was calculated based on the median platelet count during each month. For each participant, the percentage of time with platelet response during the first 6 months was calculated as the number of months a platelet response was observed divided by the total number of months response was assessed. The efficacy analysis set included all enrolled participants who received at least 1 dose of romiplostim.
    End point type
    Primary
    End point timeframe
    Week 2 to Month 6, platelet response was assessed every week.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented in the data table per protocol.
    End point values
    		 Romiplostim
    Number of subjects analysed
    203
    Units: percentage of time
        median (inter-quartile range (Q1-Q3))
    50.00 (16.67 to 83.33)
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Developed Collagen after Exposure to Romiplostim

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    End point title
    		 Percentage of Participants Who Developed Collagen after Exposure to Romiplostim [2]
    End point description
    The percentage of participants who developed collagen as evidenced by trichrome staining, defined as a Grade 4 on the modified Bauermeister grading scale: 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) The bone marrow analysis set includes participants who received at least 1 dose of romiplostim, who were recruited within the protocol supplement for the EU, Switzerland and Turkey and who had at least 1 bone marrow biopsy during the study after initiation of study treatment. Participants with available core biopsy results are included in the analysis.
    End point type
    Primary
    End point timeframe
    Year 1 (Cohort 1) and year 2 (Cohort 2)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented in the data table per protocol.
    End point values
    		 Cohort 1 Cohort 2
    Number of subjects analysed
    27
    36
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 12.8)
    0.0 (0.0 to 9.7)
    No statistical analyses for this end point

    Primary: Percentage of Participants with Increased Modified Bauermeister Grade

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    End point title
    		 Percentage of Participants with Increased Modified Bauermeister Grade [3]
    End point description
    The percentage of participants with an increased modified Bauermeister grade defined as an increase by ≥ 2 severity grades or an increase to grade 4 (i.e., grade 0 to 2-4, grade 1 to 3-4, grade 2 to 4, or grade 3 to 4 over baseline). The modified Bauermeister grading scale: 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) Participants in the bone marrow analysis set with available core biopsy results are included in the analysis. Participants without an evaluable baseline result were assumed to have a baseline modified Bauermeister score of 0.
    End point type
    Primary
    End point timeframe
    Baseline, year 1 (Cohort 1) and year 2 (Cohort 2)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented in the data table per protocol.
    End point values
    		 Cohort 1 Cohort 2
    Number of subjects analysed
    27
    36
    Units: percentage of participants
        number (confidence interval 95%)
    3.7 (0.1 to 19.0)
    0.0 (0.0 to 9.7)
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Developed Bone Marrow Abnormalities

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    End point title
    		 Percentage of Participants Who Developed Bone Marrow Abnormalities [4]
    End point description
    The percentage of participants with bone marrow abnormalities (eg, myelodysplastic syndrome, monosomy 7) based on analysis of bone marrow biopsy and aspirate samples using cytogenetics and fluorescence in situ hybridization. Participants in the bone marrow analysis set with an on-study bone marrow abnormality assessment are included in the analysis.
    End point type
    Primary
    End point timeframe
    Year 1 (Cohort 1) and year 2 (Cohort 2)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented in the data table per protocol.
    End point values
    		 Cohort 1 Cohort 2
    Number of subjects analysed
    27
    31
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 12.8)
    0.0 (0.0 to 11.2)
    No statistical analyses for this end point

    Secondary: Percentage of Time With a Platelet Response During the Overall Treatment Period

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    End point title
    		 Percentage of Time With a Platelet Response During the Overall Treatment Period
    End point description
    Platelet response was defined as a platelet count of ≥ 50 x 10⁹ cells/L with no rescue medication use in the past 4 weeks. Monthly platelet response was calculated based on the median platelet count during each month. For each participant, the percentage of time with platelet response was calculated as the number of months a platelet response was observed divided by the total number of months response was assessed. The efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    From week 2 to the end of the treatment period, 36 months
    End point values
    		 Romiplostim
    Number of subjects analysed
    203
    Units: percentage of time
        median (inter-quartile range (Q1-Q3))
    78.21 (26.67 to 90.39)
    No statistical analyses for this end point

    Secondary: Percentage of Time With an Increase in Platelet Count ≥ 20 x 10⁹ Cells/L Above Baseline

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    End point title
    		 Percentage of Time With an Increase in Platelet Count ≥ 20 x 10⁹ Cells/L Above Baseline
    End point description
    The percentage of time with an increase in platelet count ≥ 20 x 10⁹ cells/L above baseline from week 2 until the end of the treatment period without rescue medication use within the past 4 weeks. For each participant, the percentage of time with an increase in platelet count ≥ 20 x10⁹ cells/L above baseline was calculated as the number of months the median platelet count was ≥ 20 x10⁹ cells/L above baseline divided by the total number of months assessed. The efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and from week 2 to month 36
    End point values
    		 Romiplostim
    Number of subjects analysed
    203
    Units: percentage of time
        median (inter-quartile range (Q1-Q3))
    80.13 (39.13 to 92.31)
    No statistical analyses for this end point

    Secondary: Number of Participants Reporting Use of Rescue Medications for ITP During the Treatment Period

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    End point title
    		 Number of Participants Reporting Use of Rescue Medications for ITP During the Treatment Period
    End point description
    Rescue medication is defined as any medication or transfusion, other than romiplostim and excluded medications, that is administered after enrollment to the participant with the intent of raising platelet counts or to prevent bleeding and includes concomitant medications for ITP in which the dose and/or schedule was increased. Permitted rescue medications included the following: • corticosteroids • platelet transfusions • Intravenous immunoglobulin (IVIG) • azathioprine • anti-D immunoglobulin • danazol The efficacy analysis set was used for this analysis.
    End point type
    Secondary
    End point timeframe
    From first dose of romiplostim to the end of the treatment period, 36 months
    End point values
    		 Romiplostim
    Number of subjects analysed
    203
    Units: participants
    60
    No statistical analyses for this end point

    Secondary: Number of Participants Who Developed Anti-Romiplostim or Anti-Thrombopoietin Neutralizing Antibodies

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    End point title
    		 Number of Participants Who Developed Anti-Romiplostim or Anti-Thrombopoietin Neutralizing Antibodies
    End point description
    Blood samples were first tested for the presence of binding antibodies to romiplostim or the peptide portion of romiplostim, and to endogenous thrombopoietin (eTPO). Samples testing positive for binding antibodies were then tested for neutralizing antibodies by assessing their ability to neutralize romiplostim and/or eTPO in a cell-based bioassay. Participants who developed neutralizing antibodies are those who had a postbaseline positive result with a negative or no result at baseline. Transient is defined as a negative result at the participant's last time point tested within the study period. Participants who received at least 1 dose of romiplostim and with a post-baseline antibody result are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 12, week 52 and every 24 weeks thereafter up to month 36
    End point values
    		 Romiplostim
    Number of subjects analysed
    203
    Units: participants
        Anti-romiplostim neutralizing antibodies
    7
        Transient anti-romiplostim neutralizing antibodies
    4
        Anti-eTPO neutralizing antibodies
    1
        Transient anti-eTPO neutralizing antibodies
    1
    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
    An adverse event (AE) was defined as any untoward medical occurrence in a clinical trial participant, which does not necessarily have a causal relationship with study treatment. A serious adverse event (SAE) was defined as an AE that met at least 1 of the following criteria: • fatal • life threatening • required in-patient hospitalization or prolongation of existing hospitalization • resulted in persistent or significant disability/incapacity • congenital anomaly/birth defect • other medically important serious event Adverse events were graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 grading scale, where Grade 1 = mild AE; Grade 2 = moderate AE; Grade 3 = severe AE; Grade 4 = life-threatening or disabling; Grade 5 = death related to AE. Participants who received at least 1 dose of romiplostim are included in the analysis.
    End point type
    Secondary
    End point timeframe
    SAEs were collected from Screening through end-of-study follow-up (up to 38 months). Nonserious AEs were collected from first to last dose of study drug during the treatment period (up to 36 months).
    End point values
    		 Romiplostim
    Number of subjects analysed
    203
    Units: participants
        Any adverse event (AE)
    193
        Serious adverse events (SAE)
    60
        AEs leading to discontinuation of romiplostim
    15
        Adverse event Grade ≥ 3
    66
        Adverse event Grade ≥ 4
    19
        Adverse event Grade ≥ 5
    0
        Treatment-related adverse events (TRAE)
    56
        Treatment-related serious adverse events
    8
        TRAEs leading to discontinuation of romiplostim
    8
        Treatment-related adverse events Grade ≥ 3
    8
        Treatment-related adverse events Grade ≥ 4
    0
        Treatment-related adverse events Grade ≥ 5
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Developed Increased Reticulin

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    End point title
    		 Percentage of Participants who Developed Increased Reticulin
    End point description
    The percentage of participants with increased reticulin as evidenced by silver staining and defined as any increase from baseline in the modified Bauermeister grade: 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) Participants in the bone marrow analysis set with available core biopsy results are included in the analysis. Participants without an evaluable baseline result were assumed to have a baseline modified Bauermeister score of 0.
    End point type
    Secondary
    End point timeframe
    Baseline, year 1 (Cohort 1) and year 2 (Cohort 2)
    End point values
    		 Cohort 1 Cohort 2
    Number of subjects analysed
    27
    36
    Units: percentage of participants
        number (confidence interval 95%)
    18.5 (6.3 to 38.1)
    47.2 (30.4 to 64.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs were collected from Screening through end-of-study follow-up (up to 38 months). Nonserious AEs were collected from first to last dose of study drug during the treatment period (up to 36 months).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    ROMIPLOSTIM
    Reporting group description
    		 Participants received romiplostim administered weekly by subcutaneous injection for up to 3 years. The starting dose was 1 µg/kg titrated in 1 µg/kg increments up to a maximum of 10 µg/kg to reach a target platelet count ≥ 50 x 10⁹/L.

    Serious adverse events
    		 ROMIPLOSTIM
    Total subjects affected by serious adverse events
         subjects affected / exposed
    60 / 203 (29.56%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Polymenorrhoea
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Varicocele
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    12 / 203 (5.91%)
         occurrences causally related to treatment / all
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Status asthmaticus
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Arthroscopy
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood urine present
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutralising antibodies positive
         subjects affected / exposed
    4 / 203 (1.97%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    10 / 203 (4.93%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Evans syndrome
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic disorder
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 203 (1.97%)
         occurrences causally related to treatment / all
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenic purpura
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Gingival bleeding
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth impacted
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage subcutaneous
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Petechiae
         subjects affected / exposed
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Purpura
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lupus nephritis
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mixed connective tissue disease
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Otitis externa
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis media acute
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal abscess
         subjects affected / exposed
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ROMIPLOSTIM
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    183 / 203 (90.15%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    13 / 203 (6.40%)
         occurrences all number
    15
    Contusion
         subjects affected / exposed
    40 / 203 (19.70%)
         occurrences all number
    365
    Skin laceration
         subjects affected / exposed
    12 / 203 (5.91%)
         occurrences all number
    13
    Limb injury
         subjects affected / exposed
    11 / 203 (5.42%)
         occurrences all number
    14
    Vascular disorders
    Haematoma
         subjects affected / exposed
    42 / 203 (20.69%)
         occurrences all number
    164
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    14 / 203 (6.90%)
         occurrences all number
    19
    Headache
         subjects affected / exposed
    78 / 203 (38.42%)
         occurrences all number
    334
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 203 (6.40%)
         occurrences all number
    24
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    19 / 203 (9.36%)
         occurrences all number
    25
    Pyrexia
         subjects affected / exposed
    65 / 203 (32.02%)
         occurrences all number
    143
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    15 / 203 (7.39%)
         occurrences all number
    21
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    12 / 203 (5.91%)
         occurrences all number
    16
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    29 / 203 (14.29%)
         occurrences all number
    45
    Abdominal pain upper
         subjects affected / exposed
    39 / 203 (19.21%)
         occurrences all number
    65
    Gingival bleeding
         subjects affected / exposed
    21 / 203 (10.34%)
         occurrences all number
    29
    Diarrhoea
         subjects affected / exposed
    38 / 203 (18.72%)
         occurrences all number
    94
    Mouth haemorrhage
         subjects affected / exposed
    16 / 203 (7.88%)
         occurrences all number
    29
    Nausea
         subjects affected / exposed
    37 / 203 (18.23%)
         occurrences all number
    66
    Vomiting
         subjects affected / exposed
    47 / 203 (23.15%)
         occurrences all number
    89
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    52 / 203 (25.62%)
         occurrences all number
    125
    Nasal congestion
         subjects affected / exposed
    18 / 203 (8.87%)
         occurrences all number
    30
    Epistaxis
         subjects affected / exposed
    77 / 203 (37.93%)
         occurrences all number
    319
    Oropharyngeal pain
         subjects affected / exposed
    37 / 203 (18.23%)
         occurrences all number
    73
    Rhinorrhoea
         subjects affected / exposed
    27 / 203 (13.30%)
         occurrences all number
    46
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    19 / 203 (9.36%)
         occurrences all number
    55
    Petechiae
         subjects affected / exposed
    48 / 203 (23.65%)
         occurrences all number
    192
    Rash
         subjects affected / exposed
    27 / 203 (13.30%)
         occurrences all number
    33
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    23 / 203 (11.33%)
         occurrences all number
    35
    Pain in extremity
         subjects affected / exposed
    22 / 203 (10.84%)
         occurrences all number
    39
    Infections and infestations
    Ear infection
         subjects affected / exposed
    15 / 203 (7.39%)
         occurrences all number
    18
    Conjunctivitis
         subjects affected / exposed
    13 / 203 (6.40%)
         occurrences all number
    15
    Gastroenteritis
         subjects affected / exposed
    19 / 203 (9.36%)
         occurrences all number
    25
    Influenza
         subjects affected / exposed
    18 / 203 (8.87%)
         occurrences all number
    26
    Nasopharyngitis
         subjects affected / exposed
    75 / 203 (36.95%)
         occurrences all number
    191
    Rhinitis
         subjects affected / exposed
    40 / 203 (19.70%)
         occurrences all number
    69
    Pharyngitis
         subjects affected / exposed
    32 / 203 (15.76%)
         occurrences all number
    56
    Tonsillitis
         subjects affected / exposed
    15 / 203 (7.39%)
         occurrences all number
    16
    Viral infection
         subjects affected / exposed
    21 / 203 (10.34%)
         occurrences all number
    54
    Upper respiratory tract infection
         subjects affected / exposed
    39 / 203 (19.21%)
         occurrences all number
    107
    Sinusitis
         subjects affected / exposed
    11 / 203 (5.42%)
         occurrences all number
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jul 2014
    As a result of regulatory reviews, additional routine monitoring has been added to the protocol. This amendment includes the following changes: - to update the inclusion criteria to include hematologic, renal, and liver criteria - to add pregnancy monitoring as applicable every 12 weeks and at the EOT visit
    15 Aug 2014
    - Exclusion criteria were modified to allow prior use of eltrombopag within 4 weeks of enrollment. - A correction was made to the dose adjustment rules in the Table 1. - Removal of reticulocytes from the laboratory specimens. - "Protocol specified criteria" were added to Section 8.2.1 Reasons for Removal From Treatment and Section 8.2.2 Reasons for Removal From Study. - Serious adverse event completion instructions (Appendix A) for faxed forms were updated.

    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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    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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