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    Clinical Trial Results:
    A 12-Week, Randomized, Double-Blind, Olive Oil-Controlled Phase 3 Study to Assess the Efficacy and Safety of EPANOVA® in Subjects With Severe Hypertriglyceridemia (EVOLVE II)

    Summary
    EudraCT number
    		 2013-004682-14
    Trial protocol
    		 HU   CZ   NL   DK  
    Global end of trial date
    23 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Mar 2016
    First version publication date
    16 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5880C00001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Södertälje, Södertälje, Sweden, SE-151 85
    Public contact
    Hong Yang, Study Statistician, AstraZeneca AB, +46 (0)317762397, hong.yang1@astrazeneca.com
    Scientific contact
    Torbjörn Lundström, Global Clinical Lead Epanova, AstraZeneca AB, +46 (0)317762397, hong.yang1@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    31 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study investigated the efficacy and safety of Epanova in subjects with severe hypertriglyceridemia (ie, TG levels ≥500 mg/dL [5.65 mmol/L] and <2500 mg/dL [28.25 mmol/L]). However, in Canada, only subjects with TG ≥500 mg/dL (5.65 mmol/L) and <2000 mg/d(22.60 mmol/L) at screening were eligible for enrollment.
    Protection of trial subjects
    ETHICS 1 Institutional Review Board The Clinical Study Protocol and informed consent document were submitted to and approved by the duly constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC) for each center prior to initiation of the study. A copy of the letter of approval and the IRB/IEC membership roster were received by the Sponsor prior to any drug shipment. See Appendix 16.1.3 for a list of IRBs/IECs consulted for this study. 2 Ethical Conduct of the Study The study was conducted in accordance with the Declaration of Helsinki and with all applicable laws and regulations of the locale and country where the study was conducted, and in compliance with Good Clinical Practice Guidelines. 3 Subject Information and Consent The rationale of the study, procedural details, and investigational goals were explained to each subject, along with potential risks and benefits. Each subject was assured of his/her right to withdraw from the study at any time. Prior to the initiation of any study procedures, each subject signed and dated an approved informed consent form (Appendix 16.1.3). The original was kept on file by the Investigator with the subject’s records, and a copy was given to each subject.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Dec 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 44
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    Denmark: 19
    Country: Number of subjects enrolled
    Hungary: 55
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Russian Federation: 35
    Worldwide total number of subjects
    162
    EEA total number of subjects
    80
    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)
    149
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The recruitment was planned at 43 sites, and in total, 162 were randomized in a 1:1 ratio to two treatment groups, Epanova (n=81) and Olive Oil (n=81). Randomization of subjects was stratified by two factors: 1. use of lipid-altering drugs (yes, no), and 2. Qualifying triglycerides values below or above 885 mg/dL.

    Pre-assignment
    Screening details
    		 Not applicable

    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
    		 Investigator, Monitor, Subject, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Epanova
    Arm description
    		 2g once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Epanova
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2g once daily (QD)

    Arm title
    		 Olive Oil
    Arm description
    		 2g once daily (QD)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Olive Oil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2g once daily (QD)

    Number of subjects in period 1
    		Epanova Olive Oil
    Started
    81
    81
    Completed
    80
    76
    Not completed
    1
    5
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    -
    2
         Protocol deviation
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Epanova
    Reporting group description
    		 2g once daily

    Reporting group title
    Olive Oil
    Reporting group description
    		 2g once daily (QD)

    Reporting group values
    		 Epanova Olive Oil Total
    Number of subjects
    		 81 81 162
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 74 75 149
        From 65-84 years
    		 7 6 13
        85 years and over
    		 0 0 0
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 50.3 ( 10.6 ) 50 ( 10.88 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 16 19 35
        Male
    		 65 62 127
    Lipid-altering drug use
    Units: Subjects
        Yes
    		 36 37 73
        No
    		 45 44 89
    At least 1 qualifying TG category > 885 mg/dL
    Units: Subjects
        No
    		 28 29 57
        Yes
    		 53 52 105

    End points

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    End points reporting groups
    Reporting group title
    Epanova
    Reporting group description
    		 2g once daily

    Reporting group title
    Olive Oil
    Reporting group description
    		 2g once daily (QD)

    Primary: Percent Change in Triglyceride (mg/dL) for all Subjects in the Full Analysis Set (FAS)

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    End point title
    		 Percent Change in Triglyceride (mg/dL) for all Subjects in the Full Analysis Set (FAS)
    End point description
    This primary endpoint was tested in parallel together with the first of the secondary endpoints, each at 0.025 Type I error rate.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 12 Endpoint
    End point values
    		 Epanova Olive Oil
    Number of subjects analysed
    81
    81
    Units: Percentage of Change (%)
        median (inter-quartile range (Q1-Q3))
    -28.1 (-42.1 to -5.5)
    -10.2 (-36.4 to 23)
    Statistical analysis title
    		 Treatment Comparison
    Statistical analysis description
    Treatment comparison on percent change in Triglyceride from baseline to Week 12 endpoint of Epanova 2 g QD compared to olive oil 2 g QD for all subjects in the FAS
    Comparison groups
    Epanova v Olive Oil
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.017
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -14.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.2
         upper limit
    		 -2.8
    Notes
    [1] - 1. Main analysis with missing values imputed using probabilities of missing estimated from logistic regression.2. The estimated median difference and its 95% CI were based on Hodges Lehmann procedure.

    Secondary: 1. Percent Change in Triglyceride (mg/dL) for Subjects in the FAS with at Least 1 Qualifying TG >885 mg/dL and <2500 mg/dL

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    End point title
    		 1. Percent Change in Triglyceride (mg/dL) for Subjects in the FAS with at Least 1 Qualifying TG >885 mg/dL and <2500 mg/dL
    End point description
    This first secondary endpoint was tested in parallel together with the primary endpoint, each at 0.025 Type I error rate.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12 Endpoint
    End point values
    		 Epanova Olive Oil
    Number of subjects analysed
    53
    52
    Units: Percentage of Change (%)
        median (inter-quartile range (Q1-Q3))
    -37.5 (-46.1 to -18.1)
    -9.3 (-36.3 to 27)
    Statistical analysis title
    		 Treatment Comparison
    Statistical analysis description
    Treatment comparison on percent change in Triglyceride from baseline to Week 12 endpoint of Epanova 2 g QD compared to olive oil 2 g QD for Subjects in the FAS with at Least 1 Qualifying TG >885 mg/dL and <2500 mg/dL
    Comparison groups
    Epanova v Olive Oil
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0008
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -26.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.5
         upper limit
    		 -11.5
    Notes
    [2] - 1. Missing values were imputed using probabilities of missing estimated from logistic regression.2. The estimated median difference and its 95% CI were based on Hodges Lehmann procedure.

    Secondary: 2. Percent Change in Non-High-Density Lipoprotein Cholesterol (mg/dL) for all Subjects in the Full Analysis Set (FAS)

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    End point title
    		 2. Percent Change in Non-High-Density Lipoprotein Cholesterol (mg/dL) for all Subjects in the Full Analysis Set (FAS)
    End point description
    This secondary endpoint, together with the 3rd. and 4th secondary ones, was treated as the core secondary, and the p value from the hypothesis test on its treatment comparison was adjusted by using Hommel's procedure.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12 Endpoint
    End point values
    		 Epanova Olive Oil
    Number of subjects analysed
    81
    81
    Units: Percentage of Change (%)
        median (inter-quartile range (Q1-Q3))
    -8.8 (-15.7 to -1.4)
    0.4 (-13.5 to 14.2)
    Statistical analysis title
    		 Treatment Comparison
    Statistical analysis description
    Treatment comparison on percent change in non-high-density lipoprotein cholesterol (mg/dL) from baseline to Week 12 endpoint of Epanova 2 g QD compared to olive oil 2 g QD for subjects in the FAS
    Comparison groups
    Epanova v Olive Oil
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.018 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.8
         upper limit
    		 -2.8
    Notes
    [3] - 1. Missing values were imputed using probabilities of missing estimated from logistic regression.2. The estimated median difference and its 95% CI were based on Hodges Lehmann procedure.
    [4] - Adjusted by using Hommel's procedure

    Secondary: 3. Percent Change in High-Density Lipoprotein Cholesterol (mg/dL) for all Subjects in the Full Analysis Set (FAS)

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    End point title
    		 3. Percent Change in High-Density Lipoprotein Cholesterol (mg/dL) for all Subjects in the Full Analysis Set (FAS)
    End point description
    1. Missing values were imputed using probabilities of missing estimated from logistic regression.2. The estimated median difference and its 95% CI were based on Hodges Lehmann procedure.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12 Endpoint
    End point values
    		 Epanova Olive Oil
    Number of subjects analysed
    81
    81
    Units: Percentage of Change (%)
        median (inter-quartile range (Q1-Q3))
    3.4 (-5.1 to 12.5)
    3.1 (-6.3 to 10.9)
    Statistical analysis title
    		 Treatment Comparison
    Statistical analysis description
    Treatment comparison on percent change in high-density lipoprotein cholesterol (mg/dL) from baseline to Week 12 endpoint of Epanova 2 g QD compared to olive oil 2 g QD for subjects in the FAS
    Comparison groups
    Epanova v Olive Oil
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.7117 [6]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 4.9
    Notes
    [5] - The estimated median difference and its 95% CI were based on Hodges Lehmann procedure.
    [6] - Adjusted by using Hommel's procedure

    Secondary: 4. Percent Change in triglyceride (mg/dL) for subjects in the FAS with biochemically defined Fredrickson Type V (triglyceride/very-low-density lipoprotein cholesterol ≥6)

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    End point title
    		 4. Percent Change in triglyceride (mg/dL) for subjects in the FAS with biochemically defined Fredrickson Type V (triglyceride/very-low-density lipoprotein cholesterol ≥6)
    End point description
    1. Missing values were imputed using probabilities of missing estimated from logistic regression.2. The estimated median difference and its 95% CI were based on Hodges Lehmann procedure.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12 Endpoint
    End point values
    		 Epanova Olive Oil
    Number of subjects analysed
    55
    57
    Units: Percentage of Change (%)
        median (inter-quartile range (Q1-Q3))
    -24.7 (-43.3 to -2.8)
    -12.4 (-38.8 to 14.2)
    Statistical analysis title
    		 Treatment Comparison
    Statistical analysis description
    Treatment comparison on percent change in triglyceride (mg/dL) from baseline to Week 12 endpoint of Epanova 2 g QD compared to olive oil 2 g QD for subjects in the FAS with biochemically defined Fredrickson Type V (triglyceride/very-low-density lipoprotein cholesterol ≥6)
    Comparison groups
    Epanova v Olive Oil
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.3034 [8]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -10.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.9
         upper limit
    		 3.5
    Notes
    [7] - 1. Missing values were imputed using probabilities of missing estimated from logistic regression.2. The estimated median difference and its 95% CI were based on Hodges Lehmann procedure.
    [8] - Adjusted by using Hommel's procedure

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline to End of Trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Olive Oil
    Reporting group description
    		 2g once daily (QD)

    Reporting group title
    Epanova
    Reporting group description
    		 2g once daily (QD)

    Serious adverse events
    		 Olive Oil Epanova
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 81 (1.23%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Rectal haemorrhage
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         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
    		 Olive Oil Epanova
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 81 (34.57%)
    29 / 81 (35.80%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    All neoplasms benign, malignant and unspecified (incl cysts and polyps)
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    Lipoma
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    Vascular disorders
    All vascular disorders
         subjects affected / exposed
    1 / 81 (1.23%)
    3 / 81 (3.70%)
         occurrences all number
    1
    3
    Hypertension
         subjects affected / exposed
    0 / 81 (0.00%)
    3 / 81 (3.70%)
         occurrences all number
    0
    3
    Flushing
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    All general disorders and administration site conditions
         subjects affected / exposed
    2 / 81 (2.47%)
    3 / 81 (3.70%)
         occurrences all number
    3
    3
    Fatigue
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 81 (2.47%)
         occurrences all number
    1
    2
    Chills
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Feeling hot
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    All respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    2 / 81 (2.47%)
    3 / 81 (3.70%)
         occurrences all number
    2
    4
    Nasal congestion
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 81 (1.23%)
         occurrences all number
    2
    1
    Rhinitis allergi
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Psychiatric disorders
    All psychiatric disorders
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    Depression
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Anxiety
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Investigations
    All investigations
         subjects affected / exposed
    3 / 81 (3.70%)
    4 / 81 (4.94%)
         occurrences all number
    4
    5
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Blood glucose increased
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    Gastric pH decreased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    All injury, poisoning and procedural complications
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    Clavicle fracture
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Tooth fracture
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    All cardiac disorders
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 81 (1.23%)
         occurrences all number
    2
    1
    Coronary artery disease
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Angina pectoris
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    All nervous system disorders
         subjects affected / exposed
    3 / 81 (3.70%)
    5 / 81 (6.17%)
         occurrences all number
    6
    5
    Dysgeusia
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    0
    2
    Dizziness
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 81 (1.23%)
         occurrences all number
    3
    1
    Headache
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 81 (1.23%)
         occurrences all number
    3
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    All ear and labyrinth disorders
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    Vertigo
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Vertigo positional
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 81 (6.17%)
    5 / 81 (6.17%)
         occurrences all number
    6
    5
    Eructation
         subjects affected / exposed
    0 / 81 (0.00%)
    3 / 81 (3.70%)
         occurrences all number
    0
    3
    Constipation
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    0
    2
    Dyspepsia
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    Flatulence
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Food poisoning
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 81 (1.23%)
         occurrences all number
    2
    1
    Pancreatitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    Abdominal distension
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    All gastrointestinal disorders
         subjects affected / exposed
    7 / 81 (8.64%)
    12 / 81 (14.81%)
         occurrences all number
    15
    17
    Hepatobiliary disorders
    All hepatobiliary disorders
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Cholelithiasis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    All skin and subcutaneous tissue disorders
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Acne
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    All renal and urinary disorders
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Renal impairment
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    All musculoskeletal and connective tissue disorders
         subjects affected / exposed
    5 / 81 (6.17%)
    0 / 81 (0.00%)
         occurrences all number
    6
    0
    Arthralgia
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Gouty arthritis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    All infections and infestations
         subjects affected / exposed
    6 / 81 (7.41%)
    10 / 81 (12.35%)
         occurrences all number
    7
    11
    Nasopharyngitis
         subjects affected / exposed
    1 / 81 (1.23%)
    3 / 81 (3.70%)
         occurrences all number
    1
    3
    Bronchitis
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    Erysipelas
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    2
    Sialadenitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 81 (3.70%)
    1 / 81 (1.23%)
         occurrences all number
    3
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    All metabolism and nutrition disorders
         subjects affected / exposed
    5 / 81 (6.17%)
    1 / 81 (1.23%)
         occurrences all number
    5
    1
    Gout
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Decreased appetite
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Nov 2013
    Amendment 1 (Protocol V2.0)
    13 Nov 2013
    Amendment 2 (Protocol V3.0)
    23 Dec 2013
    Amendment 3 (Protocol V4.0)
    23 Jun 2014
    Amendment 3.1 (Protocol V4.1)

    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
    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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