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    Clinical Trial Results:
    A Randomized, Global, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of Once-daily Oral Avatrombopag for the Treatment of Adults with Thrombocytopenia Associated with Liver Disease Prior to an Elective Procedure

    Summary
    EudraCT number
    		 2013-000965-34
    Trial protocol
    		 BE   DE   IT   GB   AT   HU   ES   PT   PL  
    Global end of trial date
    27 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Feb 2018
    First version publication date
    14 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    E5501-G000-310
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01972529
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Ltd.
    Sponsor organisation address
    Mosquito Way, Hatfield, Hertfordshire, United Kingdom, AL10 9SN UK
    Public contact
    Medical Information, Eisai Limited, +44 08456761400, LmedInfo@eisai.net
    Scientific contact
    Medical Information, Eisai Limited, +44 08456761400, LmedInfo@eisai.net
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a global, multicenter, randomized, double-blind, placebo-controlled, parallel group study using avatrombopag to treat adults with thrombocytopenia associated with liver disease. The study will evaluate avatrombopag in the treatment of thrombocytopenia associated with liver disease prior to an elective procedure to reduce the need for platelet transfusions or any rescue procedure for bleeding due to procedural and post-procedural bleeding complications. Participants will be enrolled into 2 cohorts according to mean baseline platelet count and, within each baseline platelet count cohort will be further stratified by risk of bleeding associated with the elective procedure (low, moderate, or high) and hepatocellular carcinoma (HCC) status (Yes or No).
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Nov 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Italy: 22
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    China: 7
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Korea, Republic of: 47
    Country: Number of subjects enrolled
    Taiwan: 22
    Country: Number of subjects enrolled
    Thailand: 10
    Country: Number of subjects enrolled
    United States: 42
    Worldwide total number of subjects
    231
    EEA total number of subjects
    85
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    186
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 370 participants signed informed consent. Of these 370 participants, 139 were screening failures and 231 were randomized into the study. Of the 139 screening failures, 120 did not meet the inclusion/exclusion criteria and the other 19 participants failed due to adverse events, lost to follow-up and withdrawal of consent.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 60 mg Placebo (lower baseline platelet count)
    Arm description
    		 Participants with a baseline platelet count of less than 40 x 10^9/liter (L) took three 20 milligrams (mg) (60 mg total) matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Avatrombopag-matched placebo was administered as three 20 mg (60 mg total) tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.

    Arm title
    		 60 mg Avatrombopag, (lower baseline platelet count)
    Arm description
    		 Participants with a baseline platelet count of less than 40 x 10^9 L took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the elective procedure.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avatrombopag
    Investigational medicinal product code
    E5501
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Avatrombopag was administered as three 20 mg (60 mg total) tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.

    Arm title
    		 40 mg Placebo (higher baseline platelet count)
    Arm description
    		 Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Avatrombopag-matched placebo was administered as two 20 mg (40 mg total) tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.

    Arm title
    		 40 mg Avatrombopag (higher baseline platelet count)
    Arm description
    		 Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg tablets (40 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avatrombopag
    Investigational medicinal product code
    E5501
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Avatrombopag was administered as two 20 mg (40 mg total) tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.

    Number of subjects in period 1
    		60 mg Placebo (lower baseline platelet count) 60 mg Avatrombopag, (lower baseline platelet count) 40 mg Placebo (higher baseline platelet count) 40 mg Avatrombopag (higher baseline platelet count)
    Started
    48
    90
    34
    59
    Completed
    46
    85
    32
    55
    Not completed
    2
    5
    2
    4
         Participant choice
    -
    1
    -
    -
         Adverse event, non-fatal
    -
    1
    -
    -
         Not specified
    -
    -
    -
    2
         Withdrawal of consent
    1
    2
    -
    1
         Lost to follow-up
    1
    -
    -
    -
         Not treated
    -
    1
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    60 mg Placebo (lower baseline platelet count)
    Reporting group description
    		 Participants with a baseline platelet count of less than 40 x 10^9/liter (L) took three 20 milligrams (mg) (60 mg total) matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.

    Reporting group title
    60 mg Avatrombopag, (lower baseline platelet count)
    Reporting group description
    		 Participants with a baseline platelet count of less than 40 x 10^9 L took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the elective procedure.

    Reporting group title
    40 mg Placebo (higher baseline platelet count)
    Reporting group description
    		 Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.

    Reporting group title
    40 mg Avatrombopag (higher baseline platelet count)
    Reporting group description
    		 Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg tablets (40 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.

    Reporting group values
    		 60 mg Placebo (lower baseline platelet count) 60 mg Avatrombopag, (lower baseline platelet count) 40 mg Placebo (higher baseline platelet count) 40 mg Avatrombopag (higher baseline platelet count) Total
    Number of subjects
    		 48 90 34 59 231
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Full analysis set was defined as the group of all randomized participants.
    Units: years
        arithmetic mean (standard deviation)
    		 55.1 ( 11.02 ) 55.6 ( 9.12 ) 57.8 ( 11.05 ) 57.5 ( 10.06 ) -
    Gender categorical
    Units: Subjects
        Female
    		 16 25 10 22 73
        Male
    		 32 65 24 37 158
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 10 10 3 7 30
        Not Hispanic or Latino
    		 37 77 31 51 196
        Unknown or Not Reported
    		 1 3 0 1 5
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 18 32 15 24 89
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 0 3 0 2 5
        White
    		 28 50 19 31 128
        More than one race
    		 0 0 0 0 0
        Unknown or Not Reported
    		 2 5 0 2 9

    End points

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    End points reporting groups
    Reporting group title
    60 mg Placebo (lower baseline platelet count)
    Reporting group description
    		 Participants with a baseline platelet count of less than 40 x 10^9/liter (L) took three 20 milligrams (mg) (60 mg total) matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.

    Reporting group title
    60 mg Avatrombopag, (lower baseline platelet count)
    Reporting group description
    		 Participants with a baseline platelet count of less than 40 x 10^9 L took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the elective procedure.

    Reporting group title
    40 mg Placebo (higher baseline platelet count)
    Reporting group description
    		 Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.

    Reporting group title
    40 mg Avatrombopag (higher baseline platelet count)
    Reporting group description
    		 Participants with a baseline platelet count of greater than or equal to 40 to less than 50 x 10^9/L took two 20 mg tablets (40 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.

    Primary: Percentage of Participants Who did not Require a Platelet Transfusion or any Rescue Procedure for Bleeding after Randomization Following a Scheduled Procedure

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    End point title
    		 Percentage of Participants Who did not Require a Platelet Transfusion or any Rescue Procedure for Bleeding after Randomization Following a Scheduled Procedure
    End point description
    Responders were defined as participants who did not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure. Participants with missing information due to early withdrawal or other reasons were conservatively considered as having received a transfusion in the analysis, (i.e. a Non-responder). Full analysis Set (FAS) was analyzed and was defined as the group of all randomized participants.
    End point type
    Primary
    End point timeframe
    Baseline (Visit 2) up to 7 days following a scheduled procedure
    End point values
    		 60 mg Placebo (lower baseline platelet count) 60 mg Avatrombopag, (lower baseline platelet count) 40 mg Placebo (higher baseline platelet count) 40 mg Avatrombopag (higher baseline platelet count)
    Number of subjects analysed
    48
    90
    34
    59
    Units: Percentage of participants
        number (confidence interval 95%)
    22.9 (11.0 to 34.8)
    65.6 (55.7 to 75.4)
    38.2 (21.9 to 54.6)
    88.1 (79.9 to 96.4)
    Statistical analysis title
    		 60 mg Placebo versus 60 mg Avatrombopag
    Statistical analysis description
    The null hypothesis was that the proportion of participants not requiring a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure was the same between the 60 mg avatrombopag and matched placebo treatment groups. Difference of proportion versus (vs) placebo = proportion of Responders for avatrombopag – proportion of Responders for placebo; 95% CI is calculated based on normal approximation.
    Comparison groups
    60 mg Placebo (lower baseline platelet count) v 60 mg Avatrombopag, (lower baseline platelet count)
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference of proportion vs placebo
    Point estimate
    42.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 27.2
         upper limit
    		 58.1
    Notes
    [1] - Stratified by the risk of bleeding associated with the elective procedure within each baseline platelet count cohort.
    Statistical analysis title
    		 40 mg Placebo versus 40 mg Avatrombopag
    Statistical analysis description
    The null hypothesis was that the proportion of participants not requiring a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure was the same between the avatrombopag and placebo treatment groups. Difference of proportion vs placebo = proportion of Responders for avatrombopag - proportion of Responders for placebo; 95% CI is calculated based on normal approximation.
    Comparison groups
    40 mg Placebo (higher baseline platelet count) v 40 mg Avatrombopag (higher baseline platelet count)
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Other[Difference of proportion vs placeb
    Point estimate
    49.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 31.6
         upper limit
    		 68.2
    Notes
    [2] - Stratified by the risk of bleeding associated with the elective procedure within each baseline platelet count cohort.

    Secondary: Percentage of Participants Who Achieved a Platelet Count greater than or equal to 50 x 10^9/L on the Scheduled Procedure Day

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    End point title
    		 Percentage of Participants Who Achieved a Platelet Count greater than or equal to 50 x 10^9/L on the Scheduled Procedure Day
    End point description
    Responders were defined as participants who achieved a platelet count greater than or equal to 50 x 10^9/L on the procedure day. Participants with missing a platelet count on the procedure day were conservatively considered as not achieving a platelet count of 50 x 10^9/L in the analysis, (i.e. Non-responders). FAS was analyzed.
    End point type
    Secondary
    End point timeframe
    Day 10 to Day 13 (Visit 4)
    End point values
    		 60 mg Placebo (lower baseline platelet count) 60 mg Avatrombopag, (lower baseline platelet count) 40 mg Placebo (higher baseline platelet count) 40 mg Avatrombopag (higher baseline platelet count)
    Number of subjects analysed
    48
    90
    34
    59
    Units: Percentage of participants
        number (confidence interval 95%)
    4.2 (0.0 to 9.8)
    68.9 (59.3 to 78.5)
    20.6 (7.0 to 34.2)
    88.1 (79.9 to 96.4)
    Statistical analysis title
    		 60 mg Placebo versus 60 mg Avatrombopag
    Statistical analysis description
    The null hypothesis was that the proportion of participants not requiring a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure was the same between the avatrombopag and placebo treatment groups. Difference of proportion vs placebo = proportion of responders for avatrombopag - proportion of responders for placebo; 95% CI is calculated based on normal approximation.
    Comparison groups
    60 mg Placebo (lower baseline platelet count) v 60 mg Avatrombopag, (lower baseline platelet count)
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference of proportion vs placebo
    Point estimate
    64.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 53.6
         upper limit
    		 75.8
    Notes
    [3] - P-value is stratified by the risk of bleeding associated with the elective procedure within each baseline platelet count cohort.
    Statistical analysis title
    		 40 mg Placebo versus 40 mg Avatrombopag
    Statistical analysis description
    The null hypothesis was that the proportion of participants not requiring a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure was the same between the avatrombopag and placebo treatment groups. Difference of proportion vs placebo = proportion of responders for avatrombopag - proportion of responders for placebo; 95% CI is calculated based on normal approximation.
    Comparison groups
    40 mg Placebo (higher baseline platelet count) v 40 mg Avatrombopag (higher baseline platelet count)
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference of percentage vs placebo
    Point estimate
    67.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 51.6
         upper limit
    		 83.4
    Notes
    [4] - P-value is stratified by the risk of bleeding associated with the elective procedure within each baseline platelet count cohort.

    Secondary: Change from Baseline in Platelet Count on the Scheduled Procedure Day

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    End point title
    		 Change from Baseline in Platelet Count on the Scheduled Procedure Day
    End point description
    Last observation carried forward was used for participants with a missing platelet count on the scheduled procedure day. Platelet count was measured preprocedure and before any platelet transfusion. FAS was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) to Procedure Day 10 to Day 13 (Visit 4)
    End point values
    		 60 mg Placebo (lower baseline platelet count) 60 mg Avatrombopag, (lower baseline platelet count) 40 mg Placebo (higher baseline platelet count) 40 mg Avatrombopag (higher baseline platelet count)
    Number of subjects analysed
    48
    88
    32
    58
    Units: Platelet count x 10^9 per liter
        arithmetic mean (standard deviation)
    0.8 ( 6.36 )
    32.0 ( 25.53 )
    1.0 ( 9.30 )
    37.1 ( 27.41 )
    Statistical analysis title
    		 60 mg Placebo versus 60 mg Avatrombopag
    Statistical analysis description
    Difference in change from baseline of platelet count for avatrombopag vs placebo within each baseline platelet count cohort is based on Hodges-Lehmann estimation; 95% confidence interval is the asymptotic (Moses) CI.
    Comparison groups
    60 mg Placebo (lower baseline platelet count) v 60 mg Avatrombopag, (lower baseline platelet count)
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Difference in change of platelet count
    Point estimate
    27.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 22.5
         upper limit
    		 32.5
    Notes
    [5] - P-value is based on Wilcoxon rank sum test for each avatrombopag treatment group vs placebo within each baseline platelet count cohort.
    Statistical analysis title
    		 40 mg Placebo versus 40 mg Avatrombopag
    Statistical analysis description
    Difference in change from baseline of platelet count for avatrombopag vs placebo within each baseline platelet count cohort is based on Hodges-Lehmann estimation; 95% confidence interval is the asymptotic (Moses) CI.
    Comparison groups
    40 mg Placebo (higher baseline platelet count) v 40 mg Avatrombopag (higher baseline platelet count)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Difference in change of platelet count
    Point estimate
    33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25.5
         upper limit
    		 41.5
    Notes
    [6] - P-value is based on Wilcoxon rank sum test for each avatrombopag treatment group vs placebo within each baseline platelet count cohort.

    Secondary: Percentage of Participants with a World Health Organization (WHO) Bleeding Score greater than or equal to 2 after a Scheduled Procedure

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    End point title
    		 Percentage of Participants with a World Health Organization (WHO) Bleeding Score greater than or equal to 2 after a Scheduled Procedure
    End point description
    The severity of bleeding events was assessed by the investigator (or appropriately delegated study site personnel) using the WHO bleeding scale. The WHO bleeding scale is a clinical investigator-assessed five-point scale with Grade 0 = No bleeding, Grade 1 = Petechial bleeding, Grade 2 = Mild blood loss (clinically significant), Grade 3 = Gross blood loss (requires transfusion (severe)), and Grade 4 = Debilitating blood loss, retinal or cerebral associated with fatality. Participants with missing information are considered as having a WHO bleeding score greater than or equal to 2 in the analysis. FAS was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) up to 7 days post scheduled procedure
    End point values
    		 60 mg Placebo (lower baseline platelet count) 60 mg Avatrombopag, (lower baseline platelet count) 40 mg Placebo (higher baseline platelet count) 40 mg Avatrombopag (higher baseline platelet count)
    Number of subjects analysed
    48
    90
    34
    59
    Units: Percentage of participants
        number (not applicable)
    6.3
    5.6
    2.9
    0
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing an Adverse Event

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    End point title
    		 Number of Participants Experiencing an Adverse Event
    End point description
    Safety assessments consisted of monitoring and recording all adverse events (AEs) and serious adverse events, including platelet transfusion-related complications; routine laboratory evaluation for hematology, serum chemistry, and urine values; periodic measurement of vital signs and electrocardiograms; the performance of physical examinations; and Doppler sonography. AE severity was graded using Common Terminology Criteria for Adverse Events version 4.0, where Grade 1 = mild, Grade 2 = moderate, Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death related to the AE. All AEs graded as 4 or 5 were considered to be serious. Treatment-emergent adverse events (TEAEs) were defined as an AE that started on or after the date of first dose of study drug, up to 30 days after the last dose of study drug. Treatment-related AEs were considered by the investigator to be possibly or probably related to study drug. Safety analysis set was analyzed.
    End point type
    Secondary
    End point timeframe
    From date of first dose of study drug up to 30 days after the last dose of study drug, up to approximately 3 years
    End point values
    		 60 mg Placebo (lower baseline platelet count) 60 mg Avatrombopag, (lower baseline platelet count) 40 mg Placebo (higher baseline platelet count) 40 mg Avatrombopag (higher baseline platelet count)
    Number of subjects analysed
    48
    89
    32
    58
    Units: Participants
        TEAEs
    31
    53
    18
    31
        Treatment-related TEAEs
    7
    12
    2
    4
        Serious TEAEs
    11
    10
    1
    8
        TEAEs leading to study drug dose adjustment
    0
    2
    0
    0
        TEAEs leading to study drug withdrawal
    0
    2
    0
    0
        TEAEs leading to study drug dose reduction
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of administration of first dose up to 30 days after the last dose, up to approximately 3 years
    Adverse event reporting additional description
    Treatment-emergent adverse events and treatment-emergent serious adverse events. Adverse events were graded using Common Terminology Criteria for Adverse Events version 4. Safety analysis set included all participants who received at least 1 dose of study drug and had at least 1 post dose safety assessment. This set was analyzed “as treated'.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    60 mg Placebo (lower baseline platelet count)
    Reporting group description
    		 Participants with a baseline platelet count of less than 40x10^9/L took three 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.

    Reporting group title
    60 mg Avatrombopag, (lower baseline platelet count)
    Reporting group description
    		 Participants with a baseline platelet count of less than 40x10^9/liter (L) took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.

    Reporting group title
    40 mg Placebo (higher baseline platelet count)
    Reporting group description
    		 Participants with a baseline platelet count of greater than or equal to 40 to 50x10^9/L took two 20 mg matching placebo tablets orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.

    Reporting group title
    40 mg Avatrombopag (higher baseline platelet count)
    Reporting group description
    		 Participants with a baseline platelet count of greater than or equal to 40 to 50x10^9/L took two 20 mg tablets (40 mg total) avatrombopag (2nd generation) orally, once daily with a meal during the Treatment Period on Days 1 through 5, and 5 to 8 days prior to the scheduled procedure.

    Serious adverse events
    		 60 mg Placebo (lower baseline platelet count) 60 mg Avatrombopag, (lower baseline platelet count) 40 mg Placebo (higher baseline platelet count) 40 mg Avatrombopag (higher baseline platelet count)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 48 (22.92%)
    10 / 89 (11.24%)
    1 / 32 (3.13%)
    8 / 58 (13.79%)
         number of deaths (all causes)
    0
    0
    0
    2
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Generalised oedema
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 89 (1.12%)
    1 / 32 (3.13%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Organ dysfunction syndrome
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Clostridium test positive
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anaphylactic transfusion reaction
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Coma hepatic
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenomegaly
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress polycythaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic haemorrhage
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    1 / 32 (3.13%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    1 / 58 (1.72%)
         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
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    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 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Chronic hepatic failure
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Azotaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 89 (0.00%)
    0 / 32 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 89 (1.12%)
    0 / 32 (0.00%)
    1 / 58 (1.72%)
         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
    		 60 mg Placebo (lower baseline platelet count) 60 mg Avatrombopag, (lower baseline platelet count) 40 mg Placebo (higher baseline platelet count) 40 mg Avatrombopag (higher baseline platelet count)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 48 (27.08%)
    28 / 89 (31.46%)
    9 / 32 (28.13%)
    16 / 58 (27.59%)
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    0 / 48 (0.00%)
    6 / 89 (6.74%)
    0 / 32 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    6
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 48 (6.25%)
    5 / 89 (5.62%)
    2 / 32 (6.25%)
    6 / 58 (10.34%)
         occurrences all number
    4
    5
    2
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 48 (2.08%)
    6 / 89 (6.74%)
    1 / 32 (3.13%)
    1 / 58 (1.72%)
         occurrences all number
    1
    6
    1
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 48 (4.17%)
    3 / 89 (3.37%)
    1 / 32 (3.13%)
    3 / 58 (5.17%)
         occurrences all number
    2
    3
    1
    3
    Pyrexia
         subjects affected / exposed
    5 / 48 (10.42%)
    7 / 89 (7.87%)
    1 / 32 (3.13%)
    5 / 58 (8.62%)
         occurrences all number
    5
    7
    1
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 48 (6.25%)
    8 / 89 (8.99%)
    3 / 32 (9.38%)
    5 / 58 (8.62%)
         occurrences all number
    3
    9
    3
    5
    Dyspepsia
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 89 (0.00%)
    2 / 32 (6.25%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Nausea
         subjects affected / exposed
    2 / 48 (4.17%)
    4 / 89 (4.49%)
    2 / 32 (6.25%)
    5 / 58 (8.62%)
         occurrences all number
    3
    5
    2
    5
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 89 (0.00%)
    2 / 32 (6.25%)
    0 / 58 (0.00%)
         occurrences all number
    0
    0
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2013
    • Addition of tranexamic acid as a rescue procedure for bleeding as requested by the European Union (EU) regulatory agency.
    22 Jun 2015
    • Updates to the bleeding risk category classification and revision to the exclusion criteria based on feedback received from the investigators. • Addition of eltrombopag and romiplostim as prohibited medications due to their potential off-label use for participants who have thrombocytopenia with Chronic Liver Disease (CLD). • Addition of an evaluation for platelet aggregation to be measured at selected sites due to a request from Japan’s Pharmaceuticals and Medical Devices Agency.
    31 May 2016
    • Clarification to Inclusion Criterion #3: the word “change” was replaced with the word “increase” as requested by the Food and Drug Administration (FDA).
    02 Dec 2016
    • The third secondary endpoint, the proportion of participants with a World Health Organization (WHO) bleeding score ≥2 after randomization and up to 7 days following a scheduled procedure, was changed to an exploratory endpoint. • This amendment also reduced the sample size from 300 to 200 participants.

    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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