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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-blind, Active-controlled, Parallel-group Trial with an Open-label Extension Phase to Evaluate the Efficacy and Safety of Oral E5501 versus Eltrombopag, in Adults with Chronic ImmuneThrombocytopenia (Idiopathic Thrombocytopenic Purpura)

    Summary
    EudraCT number
    		 2011-000831-10
    Trial protocol
    		 BE   DE   AT   NL   GB   ES  
    Global end of trial date
    13 Sep 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Apr 2016
    First version publication date
    14 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    E5501-G000-305
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01433978
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ASTUTE: E5501-G000-305
    Sponsors
    Sponsor organisation name
    Eisai
    Sponsor organisation address
    155 Tice Boullevard, Woodcliff Lake, United States, 07677
    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
    29 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Sep 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Core study To compare the efficacy of avatrombopag (in addition to standard) of care to eltrombopag (in addition to standard of care) for the treatment of adult participants with chronic immune thrombocytopenia (idiopathic thrombocytopenic purpura [ITP]) as measured by durable platelet response. Open-label Extension Phase To evaluate the safety and tolerability of long-term therapy with avatrombopag in participants with chronic ITP (cITP).
    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 Conference 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 Conference on Harmonisation 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 participant 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 participant Information and Informed Consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    23
    EEA total number of subjects
    6
    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)
    17
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Out of 6 participants who entered the Open-label Extension Phase (OLE), zero participants completed the OLE phase and 6 participants discontinued the extension phase. Reason for discontinuation of participants is as follows: study termination by Sponsor (4); lack of efficacy (1); adverse event, non-fatal (1).

    Pre-assignment
    Screening details
    		 One screen-failed participant was randomized into the study in error, but not dosed.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Eltrombopag (Core Study)
    Arm description
    		 Eltrombopag was administered orally as 25 mg, 50 mg, or 75 mg in a flexible dose design for 26 weeks. Participants received blinded therapy at a starting dose of 50 mg eltrombopag once daily and they were allowed to have their dose titrated up (maximum dose of 75 mg eltrombopag) or down (minimum dose of 25 mg eltrombopag) depending on their response to study drug.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Eltrombopag
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eltrombopag tablets administered orally as 25-, 50-, or 75-mg doses, in a flexible dose design.

    Arm title
    		 Avatrombopag (Core Study)
    Arm description
    		 Avatrombopag was administered orally as 5 mg, 10 mg, 20 mg, 30 mg or 40 mg in a flexible dose design for 26 weeks. Participants received blinded therapy at a starting dose of 20 mg avatrombopag, once daily and they were allowed to have their dose titrated up (maximum dose of 40 mg avatrombopag) or down (minimum dose of 5 mg avatrombopag) depending on their response to study drug.
    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 tablets administered orally as 5-, 10-, 20-, 30-, or 40-mg doses, in a flexible dose design.

    Number of subjects in period 1
    		Eltrombopag (Core Study) Avatrombopag (Core Study)
    Started
    11
    12
    Completed
    0
    1
    Not completed
    11
    11
         Adverse event, non-fatal
    -
    1
         Study Terminated by Sponsor
    6
    9
         Lack of efficacy
    5
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Eltrombopag (Core Study)
    Reporting group description
    		 Eltrombopag was administered orally as 25 mg, 50 mg, or 75 mg in a flexible dose design for 26 weeks. Participants received blinded therapy at a starting dose of 50 mg eltrombopag once daily and they were allowed to have their dose titrated up (maximum dose of 75 mg eltrombopag) or down (minimum dose of 25 mg eltrombopag) depending on their response to study drug.

    Reporting group title
    Avatrombopag (Core Study)
    Reporting group description
    		 Avatrombopag was administered orally as 5 mg, 10 mg, 20 mg, 30 mg or 40 mg in a flexible dose design for 26 weeks. Participants received blinded therapy at a starting dose of 20 mg avatrombopag, once daily and they were allowed to have their dose titrated up (maximum dose of 40 mg avatrombopag) or down (minimum dose of 5 mg avatrombopag) depending on their response to study drug.

    Reporting group values
    		 Eltrombopag (Core Study) Avatrombopag (Core Study) Total
    Number of subjects
    		 11 12 23
    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)
    		 45.4 ( 20.09 ) 50.8 ( 23.04 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7 14
        Male
    		 4 5 9

    End points

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    End points reporting groups
    Reporting group title
    Eltrombopag (Core Study)
    Reporting group description
    		 Eltrombopag was administered orally as 25 mg, 50 mg, or 75 mg in a flexible dose design for 26 weeks. Participants received blinded therapy at a starting dose of 50 mg eltrombopag once daily and they were allowed to have their dose titrated up (maximum dose of 75 mg eltrombopag) or down (minimum dose of 25 mg eltrombopag) depending on their response to study drug.

    Reporting group title
    Avatrombopag (Core Study)
    Reporting group description
    		 Avatrombopag was administered orally as 5 mg, 10 mg, 20 mg, 30 mg or 40 mg in a flexible dose design for 26 weeks. Participants received blinded therapy at a starting dose of 20 mg avatrombopag, once daily and they were allowed to have their dose titrated up (maximum dose of 40 mg avatrombopag) or down (minimum dose of 5 mg avatrombopag) depending on their response to study drug.

    Primary: Change from Baseline in Local Platelet Count for the 6 Month Treatment Period

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    End point title
    		 Change from Baseline in Local Platelet Count for the 6 Month Treatment Period
    End point description
    Platelet responses to avatrombopag was evaluated using the platelet counts determined at local clinical laboratories. Only participants with non-missing data at both baseline and the relevant post-baseline visit are included in the change from baseline summary statistics. Standard deviation is not applicable for some of the categories, from Visit 14 to Visit 22, as the number of participants analyzed for that visit was 1 individual.
    End point type
    Primary
    End point timeframe
    Day 5, Day 8, Week 2, Week 3, Week 4, Week 6, Week 8, Week 10, Week 12, Week 14, Week 16, Week 18, Week 19, Week 20, Week 22, Week 23, Week 24, Week 25, and Week 26
    End point values
    		 Eltrombopag (Core Study) Avatrombopag (Core Study)
    Number of subjects analysed
    11
    12
    Units: 10^9/L
    arithmetic mean (standard deviation)
        Visit 3 (Day 5) N = 10, 10
    8.6 ( 17.312 )
    12.85 ( 16.054 )
        Visit 4 (Day 8) N = 11, 11
    32.5 ( 44.519 )
    47 ( 59.69 )
        Visit 5 (Week 2) N = 11, 12
    73.41 ( 79.885 )
    171.71 ( 201.736 )
        Visit 6 (Week 3) N = 10, 12
    67.2 ( 95.536 )
    114.21 ( 117.172 )
        Visit 7 (Week 4) N = 9, 12
    28.72 ( 38.437 )
    108.79 ( 217.036 )
        Visit 8 (Week 6) N = 7, 11
    57.21 ( 57.718 )
    150.68 ( 134.902 )
        Visit 9 (Week 8) N = 4, 8
    67.25 ( 46.055 )
    121.31 ( 149.04 )
        Visit 10 (Week 10) N = 3, 6
    92.67 ( 34.649 )
    126.25 ( 90.602 )
        Visit 11 (Week 12) N = 3, 5
    87.33 ( 72.616 )
    185.1 ( 115.841 )
        Visit 12 (Week 14 ) N = 3, 4
    104.33 ( 77.114 )
    159.38 ( 116.746 )
        Visit 13 (Week 16) N = 2, 4
    47.75 ( 2.475 )
    123.88 ( 124.474 )
        Visit 14 (Week 18) N = 1, 2
    107.5 ( 0 )
    46.5 ( 53.74 )
        Visit 15 (Week 19) N = 1, 2
    13.5 ( 0 )
    29.5 ( 22.627 )
        Visit 16 (Week 20) N = 0, 1
    0 ( 0 )
    50.5 ( 0 )
        Visit 18 (Week 22) N = 0, 1
    0 ( 0 )
    75.5 ( 0 )
        Visit 19 (Week 23) N = 0, 1
    0 ( 0 )
    104.5 ( 0 )
        Visit 20 (Week 24) N = 0, 1
    0 ( 0 )
    106.5 ( 0 )
        Visit 21 (Week 25) N = 0, 1
    0 ( 0 )
    120.5 ( 0 )
        Visit 22 (Week 26) N = 0, 1
    0 ( 0 )
    58.5 ( 0 )
    Statistical analysis title
    		 Superiority
    Comparison groups
    Eltrombopag (Core Study) v Avatrombopag (Core Study)
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    42.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -56.2
         upper limit
    		 140.4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 34 Weeks in the Core Study (including 26 weeks of Treatment, plus Dose Taper and Follow-up for those that did not enter the Extension Phase) and up to 104 weeks in the Extension Phase (including Dose Taper and Follow-up).
    Adverse event reporting additional description
    Treatment emergent adverse events were collected. Core Study Safety Analysis Set (SAS): All participants who received at least 1 dose of study drug and had at least 1 postdose safety assessment. OLE SAS: All participants who received at least 1 dose of avatrombopag (either in the Core or Extension Phase) and had a postdose safety assessment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Avatrombopag (Open-label Extension Phase)
    Reporting group description
    		 Participants who met the eligibility requirements for the Open-label Extension (OLE) Phase or who discontinued the Core Study early because of lack of treatment effect were eligible to continue into the OLE Phase for up to 104 weeks of open-label avatrombopag therapy. Participants entering the OLE from the Core Study received a starting dose of open-label avatrombopag that was determined by the last dose of study drug at the End of Treatment (EOT) Visit (Visit 22) of the Core Study. Participants who discontinued the Core Study early because of lack of treatment effect and entered the OLE received open-label avatrombopag at a starting dose of 20 mg once daily of open-label avatrombopag.

    Reporting group title
    Eltrombopag (Core Study)
    Reporting group description
    		 Eltrombopag was administered orally as 25 mg, 50 mg, or 75 mg in a flexible dose design for 26 weeks. Participants received blinded therapy at a starting dose of 50 mg eltrombopag once daily and they were allowed to have their dose titrated up (maximum dose of 75 mg eltrombopag) or down (minimum dose of 25 mg eltrombopag) depending on their response to study drug.

    Reporting group title
    Avatrombopag (Core Study)
    Reporting group description
    		 Avatrombopag was administered orally as 5 mg, 10 mg, 20 mg, 30 mg or 40 mg in a flexible dose design for 26 weeks. Participants received blinded therapy at a starting dose of 20 mg avatrombopag, once daily and they were allowed to have their dose titrated up (maximum dose of 40 mg avatrombopag) or down (minimum dose of 5 mg avatrombopag) depending on their response to study drug.

    Serious adverse events
    		 Avatrombopag (Open-label Extension Phase) Eltrombopag (Core Study) Avatrombopag (Core Study)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 17 (23.53%)
    0 / 11 (0.00%)
    2 / 12 (16.67%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Idiopathic thrombocytopenic purpura
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Portal vein thrombosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis moraxella
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis septic
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Avatrombopag (Open-label Extension Phase) Eltrombopag (Core Study) Avatrombopag (Core Study)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 17 (94.12%)
    11 / 11 (100.00%)
    11 / 12 (91.67%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular disorders
    Raynaud's phenomenon
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 17 (29.41%)
    5 / 11 (45.45%)
    1 / 12 (8.33%)
         occurrences all number
    10
    7
    2
    Oedema peripheral
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Asthenia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Pyrexia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Menorrhagia
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 11 (18.18%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    1
    Nipple pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 11 (18.18%)
    1 / 12 (8.33%)
         occurrences all number
    2
    2
    2
    Nasal congestion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    2
    Epistaxis
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 11 (18.18%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Pleurisy
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Haemoptysis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Pneumothorax
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 17 (23.53%)
    1 / 11 (9.09%)
    3 / 12 (25.00%)
         occurrences all number
    4
    1
    3
    Sleep disorder
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    1
    Platelet count increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Weight increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphocyte count increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 11 (18.18%)
    0 / 12 (0.00%)
         occurrences all number
    2
    4
    0
    Laceration
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Muscle strain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Scratch
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Cartilage injury
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Fall
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 17 (23.53%)
    2 / 11 (18.18%)
    3 / 12 (25.00%)
         occurrences all number
    7
    2
    6
    Dysgeusia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Head discomfort
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Headache
         subjects affected / exposed
    5 / 17 (29.41%)
    3 / 11 (27.27%)
    3 / 12 (25.00%)
         occurrences all number
    10
    4
    5
    Hypoaesthesia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Paraesthesia
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 11 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    2
    Sinus headache
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Blood and lymphatic system disorders
    Idiopathic thrombocytopenic purpura
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Abnormal sensation in eye
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    0
    3
    Eye disorder
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Eye irritation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Eye pruritus
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Eye swelling
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    4
    2
    1
    Abdominal pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    Constipation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    2 / 17 (11.76%)
    3 / 11 (27.27%)
    2 / 12 (16.67%)
         occurrences all number
    2
    3
    2
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 11 (9.09%)
    2 / 12 (16.67%)
         occurrences all number
    2
    1
    2
    Glossodynia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Nausea
         subjects affected / exposed
    3 / 17 (17.65%)
    2 / 11 (18.18%)
    3 / 12 (25.00%)
         occurrences all number
    4
    2
    4
    Oral mucosal blistering
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    2
    3
    0
    Swollen tongue
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    2
    Dyspepsia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Stomatitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Discomfort
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatobiliary disorders
    Portal vein thrombosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Night sweats
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Papule
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    0
    1
    Rash pruritic
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Blood blister
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Skin haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Acne
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 11 (18.18%)
    1 / 12 (8.33%)
         occurrences all number
    2
    2
    1
    Limb discomfort
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    2
    Muscle spasms
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 11 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    3
    0
    3
    Myalgia
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 11 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    6
    0
    4
    Pain in extremity
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    5
    0
    3
    Osteonecrosis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 17 (23.53%)
    3 / 11 (27.27%)
    2 / 12 (16.67%)
         occurrences all number
    4
    3
    2
    Oral candidiasis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Bronchitis moraxella
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Thrombophlebitis septic
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Iron deficiency
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The study was terminated early on 22 Jan 2013. After much consideration, the sponsor made the decision to discontinue the study due to significant enrollment challenges. Results could not be released before 21 July 2015 due to EudraCT Sysyem issues.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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