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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
    		 2013-000934-36
    Trial protocol
    		 BE   DE   IT   ES   CZ  
    Global end of trial date
    21 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-G000-311
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01976104
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Ltd.
    Sponsor organisation address
    European Knowledge Center, Mosquitto 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
    30 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    21 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
    Spain: 4
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    China: 3
    Country: Number of subjects enrolled
    Israel: 22
    Country: Number of subjects enrolled
    Japan: 50
    Country: Number of subjects enrolled
    Mexico: 17
    Country: Number of subjects enrolled
    Romania: 13
    Country: Number of subjects enrolled
    Russian Federation: 9
    Country: Number of subjects enrolled
    United States: 42
    Worldwide total number of subjects
    204
    EEA total number of subjects
    51
    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)
    141
    From 65 to 84 years
    48
    85 years and over
    15

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 346 participants signed informed consent. Of these 346 participants, 142 were screen failures and 204 were randomized into the study. Of the 142 screen failures, 119 did not meet inclusion/exclusion criteria and 13 withdrew consent, 3 experienced an adverse event, 1 was lost to follow-up and 6 had other not specified reasons.

    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 40x10^9/liter (L) took three 20 milligrams (mg) matching placebo tablets orally, once daily with a meal on Days 1 through 5.
    Arm type
    		 Placebo

    Investigational medicinal product name
    60 mg Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants took three 20 mg matching placebo tablets orally, once daily with a meal on Days 1 through 5.

    Arm title
    		 60 mg Avatrombopag (lower baseline platelet count)
    Arm description
    		 Participants with a baseline platelet count of less than 40x10^9/L took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal on Days 1 through 5.
    Arm type
    		 Experimental

    Investigational medicinal product name
    60 mg Avatrombopag
    Investigational medicinal product code
    E5501
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal on Days 1 through 5.

    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 50x10^9/L took two 20 mg matching placebo tablets orally, once daily with a meal on Days 1 through 5.
    Arm type
    		 Placebo

    Investigational medicinal product name
    40 mg Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants took two 20 mg matching placebo tablets orally, once daily with a meal on Days 1 through 5.

    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 50x10^9/L took two 20 mg tablets (40 mg total) avatrombopag (2nd generation) orally, once daily with a meal on Days 1 through 5.
    Arm type
    		 Experimental

    Investigational medicinal product name
    40 mg Avatrombopag
    Investigational medicinal product code
    E5501
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants too two 20 mg tablets (40 mg total) avatrombopag (2nd generation) orally, once daily with a meal on Days 1 through 5.

    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
    43
    70
    33
    58
    Completed
    37
    68
    31
    55
    Not completed
    6
    2
    2
    3
         Consent withdrawn by subject
    3
    -
    -
    1
         Adverse event, non-fatal
    -
    -
    1
    -
         Unspecified
    -
    1
    -
    -
         Lost to follow-up
    3
    -
    1
    1
         Subject choice
    -
    1
    -
    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 40x10^9/liter (L) took three 20 milligrams (mg) matching placebo tablets orally, once daily with a meal on Days 1 through 5.

    Reporting group title
    60 mg Avatrombopag (lower baseline platelet count)
    Reporting group description
    		 Participants with a baseline platelet count of less than 40x10^9/L took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal on Days 1 through 5.

    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 on Days 1 through 5.

    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 on Days 1 through 5.

    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
    		 43 70 33 58 204
    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
    Units: years
        arithmetic mean (standard deviation)
    		 57.3 ( 11.98 ) 58.6 ( 14.18 ) 59.2 ( 10.31 ) 57.9 ( 11.11 ) -
    Gender categorical
    Units: Subjects
        Female
    		 16 20 16 25 77
        Male
    		 27 50 17 33 127
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 12 11 7 15 45
        Not Hispanic or Latino
    		 29 56 25 42 152
        Unknown or Not Reported
    		 2 3 1 1 7
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 10 25 8 12 55
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 2 2 0 2 6
        White
    		 27 40 24 40 131
        More than one race
    		 4 3 0 4 11
        Unknown or Not Reported
    		 0 0 1 0 1

    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 40x10^9/liter (L) took three 20 milligrams (mg) matching placebo tablets orally, once daily with a meal on Days 1 through 5.

    Reporting group title
    60 mg Avatrombopag (lower baseline platelet count)
    Reporting group description
    		 Participants with a baseline platelet count of less than 40x10^9/L took three 20 mg tablets (60 mg total) avatrombopag (2nd generation) orally, once daily with a meal on Days 1 through 5.

    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 on Days 1 through 5.

    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 on Days 1 through 5.

    Primary: Percentage of Participants Who Did Not Require a Platelet Transfusion After Randomization and up to 7 Days Following a Scheduled Procedure

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    End point title
    		 Percentage of Participants Who Did Not Require a Platelet Transfusion After Randomization and up to 7 Days 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). The Full Analysis Set (FAS) was analyzed.
    End point type
    Primary
    End point timeframe
    Randomization (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
    43
    70
    33
    58
    Units: Percentage of participants
        number (confidence interval 95%)
    34.9 (20.6 to 49.1)
    68.6 (57.7 to 79.4)
    33.3 (17.2 to 49.4)
    87.9 (79.5 to 96.3)
    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.
    Comparison groups
    60 mg Placebo (lower baseline platelet count) v 60 mg Avatrombopag (lower baseline platelet count)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0006 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference of proportion versus placebo
    Point estimate
    33.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 15.8
         upper limit
    		 51.6
    Notes
    [1] - Difference of proportion vs placebo = proportion of Responders for avatrombopag - proportion of Responders for placebo; 95% confidence interval (CI) is calculated based on normal approximation.
    [2] - Stratified by the risk of bleeding associated with the scheduled 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 60 mg avatrombopag and matched placebo treatment groups.
    Comparison groups
    40 mg Placebo (higher baseline platelet count) v 40 mg Avatrombopag (higher baseline platelet count)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference of proportion versus placebo
    Point estimate
    54.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 36.5
         upper limit
    		 72.7
    Notes
    [3] - Difference of proportion vs placebo = proportion of Responders for avatrombopag - proportion of Responders for placebo; 95% CI is calculated based on normal approximation.
    [4] - Stratified by the risk of bleeding associated with the scheduled 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 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 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 missing a platelet count on the procedure day were conservatively considered as not achieving a platelet count of 50x10^9/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
    43
    70
    33
    58
    Units: Percentage of participants
        number (confidence interval 95%)
    7.0 (0.0 to 14.6)
    67.1 (56.1 to 78.1)
    39.4 (22.7 to 56.1)
    93.1 (86.6 to 99.6)
    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.
    Comparison groups
    60 mg Placebo (lower baseline platelet count) v 60 mg Avatrombopag (lower baseline platelet count)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference of proportion versus placebo
    Point estimate
    60.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 46.8
         upper limit
    		 73.5
    Notes
    [5] - Difference of proportion vs placebo = proportion of responders for avatrombopag - proportion of responders for placebo; 95% CI is calculated based on normal approximation.
    [6] - Stratified by the risk of bleeding associated with the scheduled 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.
    Comparison groups
    40 mg Placebo (higher baseline platelet count) v 40 mg Avatrombopag (higher baseline platelet count)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.0001 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference of proportion versus placebo
    Point estimate
    53.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 35.8
         upper limit
    		 71.6
    Notes
    [7] - Difference of proportion vs placebo = proportion of responders for avatrombopag - proportion of responders for placebo; 95% CI is calculated based on normal approximation.
    [8] - Stratified by the risk of bleeding associated with the scheduled procedure within each Baseline platelet count cohort.

    Secondary: Change from baseline in platelet counts on Scheduled Procedure Day

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    End point title
    		 Change from baseline in platelet counts on 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.
    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
    43
    69
    33
    58
    Units: Platelet Count x 10^9
        arithmetic mean (standard deviation)
    3.0 ( 10.01 )
    31.3 ( 24.9 )
    5.9 ( 14.89 )
    44.9 ( 32.96 )
    Statistical analysis title
    		 60 mg Placebo 60 mg Avatrombopag
    Comparison groups
    60 mg Placebo (lower baseline platelet count) v 60 mg Avatrombopag (lower baseline platelet count)
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.0001 [10]
    Method
    		 Wilcoxon Rank Sum Test
    Parameter type
    		 Difference in change of platelet count
    Point estimate
    25.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 19.5
         upper limit
    		 32
    Notes
    [9] - Difference in change from Baseline of platelet count for avatrombopag versus placebo within each Baseline platelet count cohort was based on Hodges-Lehmann estimation; 95% CI was the asymptotic (Moses) CI
    [10] - P-value was based on Wilcoxon Rank Sum Test for each avatrombopag treatment group versus placebo within each Baseline platelet count cohort.
    Statistical analysis title
    		 40 mg Placebo versus 40 mg Avatrombopag
    Comparison groups
    40 mg Placebo (higher baseline platelet count) v 40 mg Avatrombopag (higher baseline platelet count)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.0001 [12]
    Method
    		 Wilcoxon Rank Sum Test
    Parameter type
    		 Difference in change of platelet count
    Point estimate
    36.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25.5
         upper limit
    		 45.5
    Notes
    [11] - 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% CI is the asymptotic (Moses) CI.
    [12] - P-value was based on Wilcoxon Rank Sum Test for each avatrombopag treatment group versus placebo within each Baseline platelet count cohort.

    Other pre-specified: Percentage of Participants with a World Health Organization (WHO) Bleeding Score greater than or equal to 2 after Randomization and up to 7 Days after an 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 Randomization and up to 7 Days after an 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
    Other pre-specified
    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
    43
    70
    33
    58
    Units: Percentage of participants
        number (not applicable)
    0.0
    1.4
    6.1
    1.7
    No statistical analyses for this end point

    Other pre-specified: 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 (ECGs); the performance of physical examinations; and Doppler sonography. AE severity was graded using Common Terminology Criteria for Adverse Events (CTCAE) 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.
    End point type
    Other pre-specified
    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 and 2 months
    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
    43
    70
    33
    57
    Units: Participants
    number (not applicable)
        TEAEs
    22
    36
    15
    28
        Treatment-related TEAEs
    9
    6
    2
    4
        Serious TEAEs
    1
    1
    1
    1
        TEAEs leading to study drug dose adjustment
    0
    0
    0
    0
        TEAEs leading to study drug withdrawal
    0
    0
    0
    0
        TEAEs leading to study drug dose reduction
    0
    0
    0
    0
        TEAEs leading to study drug dose interruption
    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 first dose of study drug up to 30 days after the last dose of study drug, up to approximately 3 years and 2 months
    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 (CTCAE) version 4. Safety analysis set included the group of participants who received at least 1 dose of study drug and had at least 1 post dose safety assessment.
    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 on Days 1 through 5.

    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 on Days 1 through 5.

    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 on Days 1 through 5.

    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 on Days 1 through 5.

    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
    1 / 43 (2.33%)
    1 / 70 (1.43%)
    1 / 33 (3.03%)
    1 / 57 (1.75%)
         number of deaths (all causes)
    0
    0
    1
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 70 (0.00%)
    1 / 33 (3.03%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 70 (0.00%)
    0 / 33 (0.00%)
    0 / 57 (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
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 70 (0.00%)
    1 / 33 (3.03%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 70 (1.43%)
    0 / 33 (0.00%)
    0 / 57 (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
    Ileus paralytic
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 70 (0.00%)
    0 / 33 (0.00%)
    1 / 57 (1.75%)
         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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 70 (0.00%)
    0 / 33 (0.00%)
    1 / 57 (1.75%)
         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
    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
    22 / 43 (51.16%)
    30 / 70 (42.86%)
    15 / 33 (45.45%)
    14 / 57 (24.56%)
    Injury, poisoning and procedural complications
    Transfusion reaction
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 70 (0.00%)
    2 / 33 (6.06%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 43 (6.98%)
    3 / 70 (4.29%)
    1 / 33 (3.03%)
    0 / 57 (0.00%)
         occurrences all number
    3
    3
    1
    0
    Headache
         subjects affected / exposed
    4 / 43 (9.30%)
    2 / 70 (2.86%)
    1 / 33 (3.03%)
    2 / 57 (3.51%)
         occurrences all number
    4
    3
    1
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 70 (1.43%)
    0 / 33 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    3
    1
    0
    2
    Puncture site haemorrhage
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 70 (0.00%)
    3 / 33 (9.09%)
    0 / 57 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Pyrexia
         subjects affected / exposed
    2 / 43 (4.65%)
    11 / 70 (15.71%)
    4 / 33 (12.12%)
    4 / 57 (7.02%)
         occurrences all number
    2
    13
    4
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 70 (2.86%)
    1 / 33 (3.03%)
    2 / 57 (3.51%)
         occurrences all number
    4
    2
    1
    2
    Abdominal pain upper
         subjects affected / exposed
    5 / 43 (11.63%)
    2 / 70 (2.86%)
    3 / 33 (9.09%)
    1 / 57 (1.75%)
         occurrences all number
    7
    2
    3
    1
    Diarrhoea
         subjects affected / exposed
    3 / 43 (6.98%)
    3 / 70 (4.29%)
    0 / 33 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    3
    3
    0
    2
    Nausea
         subjects affected / exposed
    5 / 43 (11.63%)
    6 / 70 (8.57%)
    2 / 33 (6.06%)
    3 / 57 (5.26%)
         occurrences all number
    5
    6
    2
    3
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 70 (0.00%)
    2 / 33 (6.06%)
    0 / 57 (0.00%)
         occurrences all number
    0
    0
    3
    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 Chromic 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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