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    Clinical Trial Results:
    A Phase 3 Randomised, Double-blind, Placebo-controlled Study to Assess the Safety and Efficacy of S-888711 (Lusutrombopag) for the Treatment of Thrombocytopenia in Patients with Chronic Liver Disease Undergoing Elective Invasive Procedures (L-PLUS 2)

    Summary
    EudraCT number
    2014-004942-91
    Trial protocol
    GB   AT   HU   DE   BE   IT   ES   CZ  
    Global end of trial date
    19 Apr 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Apr 2018
    First version publication date
    19 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1423M0634
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shionogi Ltd.
    Sponsor organisation address
    33 Kingsway, London, United Kingdom, WC2B 6UF
    Public contact
    Regulatory Affairs., Shionogi Ltd., +44 20 3053 4200, shionogiclintrials-admin@shionogi.co.jp
    Scientific contact
    Dr Nico Merante, Vice President, Clinical Development - Europe, Shionogi Ltd., +44 020 3053 4200, shionogiclintrials-admin@shionogi.co.jp
    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
    19 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of S-888711 with placebo for the treatment of thrombocytopenia in patients with CLD who are undergoing elective invasive procedures
    Protection of trial subjects
    The study was conducted in accordance with all appropriate regulatory requirements and under the IEC-approved protocol, as well as in accordance with current International Council for Harmonisation (ICH), Good Clinical Practice (GCP), all appropriate subject privacy requirements, and the ethical principles outlined in the Declaration of Helsinki (1996).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Jun 2015
    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: 8
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    Thailand: 6
    Country: Number of subjects enrolled
    Turkey: 13
    Country: Number of subjects enrolled
    Ukraine: 12
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 26
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Czech Republic: 7
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Israel: 27
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Romania: 11
    Country: Number of subjects enrolled
    Russian Federation: 5
    Worldwide total number of subjects
    215
    EEA total number of subjects
    94
    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)
    172
    From 65 to 84 years
    43
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A multi-center study conducted at 138 sites in 22 countries. A total of 215 Subjects were enrolled into the study. Number of Subjects Planned: 200 (100 per treatment group) Number of subjects Randomized: 215 (lusutrombopag, 108; placebo, 107).

    Pre-assignment
    Screening details
    A screening period (up to 28 days prior to randomization). 322 subjects were screened and 215 randomised. During the screening visit, informed consent was obtained prior to any study-related procedures.

    Pre-assignment period milestones
    Number of subjects started
    322 [1]
    Number of subjects completed
    215

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Other: 107
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The world-wide number reported is equal to the number of randomised patients and not to the pre-assignment number.
    Period 1
    Period 1 title
    Treatment Period (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
    Treatment period with lusutrombopag
    Arm description
    A treatment period of 7 days (Days 1 to 7 during which study drug was to be administered for 4 to 7 days). Once-daily treatment with lusutrombopag 3 mg or placebo was to commence on Day 1 and continue for up to 7 days. Administration of the study drug on Day 2 was to be performed ≥ 12 hours after administration on Day 1. Platelet count was to be determined on Days 5, 6, and 7 prior to the administration of study drug.
    Arm type
    Experimental

    Investigational medicinal product name
    Lusutrombopag
    Investigational medicinal product code
    S-888711
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    3 mg lusutrombopag or placebo once daily.

    Arm title
    Treatment with Placebo
    Arm description
    A treatment period of 7 days (Days 1 to 7 during which study drug was to be administered for 4 to 7 days). Once-daily treatment with lusutrombopag 3 mg or placebo was to commence on Day 1 and continue for up to 7 days. Administration of the study drug on Day 2 was to be performed ≥ 12 hours after administration on Day 1. Platelet count was to be determined on Days 5, 6, and 7 prior to the administration of study drug.
    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
    3 mg lusutrombopag or placebo once daily.

    Number of subjects in period 1
    Treatment period with lusutrombopag Treatment with Placebo
    Started
    108
    107
    Completed
    98
    102
    Not completed
    10
    5
         Other
    2
    -
         Adverse event, serious fatal
    3
    -
         Adverse event, non-fatal
    -
    1
         Consent withdrawn by subject
    4
    3
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period
    Reporting group description
    Overall, 200 subjects (93.0%) completed the study, including 98 subjects (90.7%) in the lusutrombopag group and 102 subjects (95.3%) in the placebo group.

    Reporting group values
    Treatment Period Total
    Number of subjects
    215 215
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    172 172
        From 65-84 years
    43 43
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    55.7 (19 to 83) -
    Gender categorical
    Units: Subjects
        Female
    81 81
        Male
    134 134

    End points

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    End points reporting groups
    Reporting group title
    Treatment period with lusutrombopag
    Reporting group description
    A treatment period of 7 days (Days 1 to 7 during which study drug was to be administered for 4 to 7 days). Once-daily treatment with lusutrombopag 3 mg or placebo was to commence on Day 1 and continue for up to 7 days. Administration of the study drug on Day 2 was to be performed ≥ 12 hours after administration on Day 1. Platelet count was to be determined on Days 5, 6, and 7 prior to the administration of study drug.

    Reporting group title
    Treatment with Placebo
    Reporting group description
    A treatment period of 7 days (Days 1 to 7 during which study drug was to be administered for 4 to 7 days). Once-daily treatment with lusutrombopag 3 mg or placebo was to commence on Day 1 and continue for up to 7 days. Administration of the study drug on Day 2 was to be performed ≥ 12 hours after administration on Day 1. Platelet count was to be determined on Days 5, 6, and 7 prior to the administration of study drug.

    Primary: Proportion of subjects who required no platelet transfusion

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    End point title
    Proportion of subjects who required no platelet transfusion
    End point description
    Proportion of patients who required no platelet transfusion prior to the primary invasive procedure and no rescue therapy for bleeding from randomisation through 7 days after the primary elective procedure.
    End point type
    Primary
    End point timeframe
    From randomization through 7 days after the primary invasive procedure.
    End point values
    Treatment period with lusutrombopag Treatment with Placebo
    Number of subjects analysed
    108
    107
    Units: Number of subjects
    70
    31
    Statistical analysis title
    Intention to Treat (ITT)
    Comparison groups
    Treatment period with lusutrombopag v Treatment with Placebo
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs (both serious and non-serious) were to be collected throughout the study from the time of informed consent until the patient’s final follow-up visit or 28 days after the last dose of study medication, whichever was later.
    Adverse event reporting additional description
    Adverse events were classified by system organ class (SOC) and preferred term using the MeDRA. Of the AEs reported, TEAEs (defined as those reported after administration of the first dose of study drug) were used for the analysis of safety. AEs could be spontaneously reported by the subject or elicited from non-leading questions.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    S-888711 3 mg
    Reporting group description
    A total of 109 TEAEs were reported in 51 of 107 subjects (47.7%) in Lusutrombopag groups. Headache was the only TEAE that occurred at an incidence of 5% or more in the lusutrombopag group.

    Reporting group title
    Placebo
    Reporting group description
    134 TEAEs were reported in 52 of 107 subjects (48.6%) in the placebo group. No safety concerns for lusutrombopag 3 mg compared with placebo were raised.

    Serious adverse events
    S-888711 3 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 107 (6.54%)
    7 / 107 (6.54%)
         number of deaths (all causes)
    3
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Vessel perforation
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 107 (0.93%)
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multi-organ failure
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid retention
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    S-888711 3 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 107 (43.93%)
    51 / 107 (47.66%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 107 (0.93%)
         occurrences all number
    2
    1
    Hot flush
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 107 (0.93%)
         occurrences all number
    1
    1
    Hypertensive crisis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Cryoglobulinaemia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Varicose vein
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Focal nodular hyperplasia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Hepatic neoplasm
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Colon adenoma
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 107 (2.80%)
    7 / 107 (6.54%)
         occurrences all number
    3
    7
    Oedema peripheral
         subjects affected / exposed
    3 / 107 (2.80%)
    4 / 107 (3.74%)
         occurrences all number
    3
    5
    Pyrexia
         subjects affected / exposed
    3 / 107 (2.80%)
    2 / 107 (1.87%)
         occurrences all number
    3
    2
    Asthenia
         subjects affected / exposed
    2 / 107 (1.87%)
    2 / 107 (1.87%)
         occurrences all number
    2
    2
    Chest discomfort
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Chest pain
         subjects affected / exposed
    2 / 107 (1.87%)
    1 / 107 (0.93%)
         occurrences all number
    2
    1
    Generalised oedema
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Peripheral swelling
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Metaplasia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 107 (1.87%)
         occurrences all number
    0
    2
    General physical health deterioration
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 107 (1.87%)
         occurrences all number
    0
    2
    Hyperthermia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Thirst
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 107 (0.93%)
         occurrences all number
    1
    1
    Agitation
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Tension
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Confusional state
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    3 / 107 (2.80%)
    2 / 107 (1.87%)
         occurrences all number
    3
    2
    Procedural complication
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Skin abrasion
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Postoperative fever
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Traumatic haemorrhage
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Eyelid injury
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 107 (0.93%)
    2 / 107 (1.87%)
         occurrences all number
    1
    2
    Blood bilirubin increased
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 107 (0.93%)
         occurrences all number
    1
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Blood urea increased
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Cardiac murmur
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 107 (1.87%)
         occurrences all number
    0
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Portal vein flow decreased
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 107 (0.93%)
         occurrences all number
    1
    1
    Splenomegaly
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Spleen congestion
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Leukopenia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Sinus congestion
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Pharyngeal haemorrhage
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Laryngeal discomfort
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 107 (5.61%)
    2 / 107 (1.87%)
         occurrences all number
    7
    2
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 107 (0.93%)
    2 / 107 (1.87%)
         occurrences all number
    1
    2
    Encephalopathy
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 107 (0.00%)
         occurrences all number
    2
    0
    Myelopathy
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Neurological decompensation
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Eyelid haematoma
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear haemorrhage
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 107 (1.87%)
    4 / 107 (3.74%)
         occurrences all number
    2
    4
    Upper Abdominal pain
         subjects affected / exposed
    2 / 107 (1.87%)
    3 / 107 (2.80%)
         occurrences all number
    2
    4
    Ascites
         subjects affected / exposed
    2 / 107 (1.87%)
    3 / 107 (2.80%)
         occurrences all number
    2
    3
    Diarrhoea
         subjects affected / exposed
    3 / 107 (2.80%)
    2 / 107 (1.87%)
         occurrences all number
    3
    2
    Duodenal ulcer
         subjects affected / exposed
    2 / 107 (1.87%)
    2 / 107 (1.87%)
         occurrences all number
    2
    2
    Vomiting
         subjects affected / exposed
    1 / 107 (0.93%)
    2 / 107 (1.87%)
         occurrences all number
    1
    2
    Abdominal pain lower
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Dyspepsia
         subjects affected / exposed
    2 / 107 (1.87%)
    1 / 107 (0.93%)
         occurrences all number
    2
    1
    Constipation
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 107 (0.93%)
         occurrences all number
    1
    1
    Hiatus hernia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Anorectal varices
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Abdominal distension
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Abdominal tenderness
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Peptic ulcer
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Large intestinal haemorrhage
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Abdominal pain
         subjects affected / exposed
    5 / 107 (4.67%)
    5 / 107 (4.67%)
         occurrences all number
    6
    5
    Hepatobiliary disorders
    Portal vein thrombosis
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 107 (1.87%)
         occurrences all number
    0
    2
    Acute hepatic failure
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Portal hypertension
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Cholecystitis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Cholestasis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Retrograde portal vein flow
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Dysuria
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 107 (0.93%)
    2 / 107 (1.87%)
         occurrences all number
    1
    2
    Ecchymosis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Erythema
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Hand dermatitis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    2 / 107 (1.87%)
    1 / 107 (0.93%)
         occurrences all number
    2
    1
    Back pain
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Arthralgia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Groin pain
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Myofascial pain syndrome
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 107 (0.93%)
         occurrences all number
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 107 (2.80%)
    0 / 107 (0.00%)
         occurrences all number
    3
    0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Sepsis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Urethritis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Helicobacter infection
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Anal abscess
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
         occurrences all number
    0
    1

    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.
    Non reported.
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