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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate Cardiovascular Outcomes of TAK-875, 50 mg in Addition to Standard of Care in Subjects with Type 2 Diabetes and with Cardiovascular Disease or Multiple Risk Factors for Cardiovascular Events

    Summary
    EudraCT number
    2011-001732-37
    Trial protocol
    HU   CZ   SK   DE   EE   LT   LV   GB   IT   BG   PL  
    Global end of trial date
    05 May 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Mar 2016
    First version publication date
    31 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TAK-875_306
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01609582
    WHO universal trial number (UTN)
    U1111-1129-7824
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    61 Aldwych, London, United Kingdom, WC2B 4AE
    Public contact
    Program Manager, Takeda Global Research & Development Centre (Europe) Ltd., 0044 0203116 8000, clinicaloperations@tgrd.com
    Scientific contact
    Program Manager, Takeda Global Research & Development Centre (Europe) Ltd., 0044 0203116 8000, clinicaloperations@tgrd.com
    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 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 May 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective is to demonstrate that no excess risk of cardiovascular (CV) composite events exists following treatment with TAK-875 (fasiglifam) compared with placebo when given in combination with Standard of Care in subjects with type 2 diabetes mellitus (T2DM) and clinically evident CV disease or multiple risk factors for CV events. For purposes of this study, the primary major adverse cardiovascular events (MACE) composite comprises CV death, nonfatal myocardial infarction (MI), nonfatal stroke, and hospitalization for unstable angina (with or without revascularization).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Jun 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
    Slovakia: 62
    Country: Number of subjects enrolled
    South Africa: 20
    Country: Number of subjects enrolled
    Taiwan: 62
    Country: Number of subjects enrolled
    Thailand: 61
    Country: Number of subjects enrolled
    Ukraine: 152
    Country: Number of subjects enrolled
    United Kingdom: 32
    Country: Number of subjects enrolled
    United States: 1118
    Country: Number of subjects enrolled
    Argentina: 242
    Country: Number of subjects enrolled
    Australia: 69
    Country: Number of subjects enrolled
    Bulgaria: 43
    Country: Number of subjects enrolled
    Canada: 211
    Country: Number of subjects enrolled
    Croatia: 33
    Country: Number of subjects enrolled
    Czech Republic: 112
    Country: Number of subjects enrolled
    Estonia: 24
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 60
    Country: Number of subjects enrolled
    Hong Kong: 58
    Country: Number of subjects enrolled
    Hungary: 146
    Country: Number of subjects enrolled
    Israel: 51
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Korea, Republic of: 56
    Country: Number of subjects enrolled
    Latvia: 22
    Country: Number of subjects enrolled
    Lithuania: 30
    Country: Number of subjects enrolled
    Malaysia: 61
    Country: Number of subjects enrolled
    Mexico: 52
    Country: Number of subjects enrolled
    New Zealand: 40
    Country: Number of subjects enrolled
    Peru: 35
    Country: Number of subjects enrolled
    Philippines: 49
    Country: Number of subjects enrolled
    Poland: 236
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    Russian Federation: 48
    Worldwide total number of subjects
    3207
    EEA total number of subjects
    822
    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)
    1645
    From 65 to 84 years
    1543
    85 years and over
    19

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects took part in the study at 469 investigative sites in 31 countries; 192 sites in North America, 175 in the Europe, Middle East, and Africa (EMEA) region (including Russia, Ukraine, Israel, and South Africa), 65 in the Asia Pacific region, and 37 in Latin/South America from 01 June 2012 to 05 May 2014.

    Pre-assignment
    Screening details
    Subjects with a historical diagnosis of T2DM and clinically-evident CV disease or multiple risk factors for CV events who were inadequately controlled while receiving the standard of care were enrolled in 1 of 2 treatment groups: placebo; fasiglifam 50 milligram (mg).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Fasiglifam placebo-matching tablet, orally, once daily for up to 588 days.
    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
    Fasiglifam placebo-matching tablet, orally, once daily for up to 588 days.

    Arm title
    Fasiglifam 50 mg
    Arm description
    Fasiglifam 50 mg, tablet, orally, once daily for up to 582 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Fasiglifam
    Investigational medicinal product code
    Other name
    TAK-875
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Fasiglifam 50 mg, tablet, orally, once daily for up to 582 days.

    Number of subjects in period 1
    Placebo Fasiglifam 50 mg
    Started
    1603
    1604
    Treated
    1603
    1601
    Completed
    0
    0
    Not completed
    1603
    1604
         Other
    9
    10
         Adverse event
    20
    18
         Withdrawal by subject
    21
    15
         Study terminated by sponsor
    1543
    1548
         Randomized, but not treated
    -
    3
         Lost to follow-up
    10
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Fasiglifam placebo-matching tablet, orally, once daily for up to 588 days.

    Reporting group title
    Fasiglifam 50 mg
    Reporting group description
    Fasiglifam 50 mg, tablet, orally, once daily for up to 582 days.

    Reporting group values
    Placebo Fasiglifam 50 mg Total
    Number of subjects
    1603 1604 3207
    Age categorical
    Units: Subjects
        Less than (<) 65 years
    794 851 1645
        Greater than or equal to (>=) 65 years
    809 753 1562
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.9 ± 9.03 63.4 ± 9.2 -
    Gender categorical
    Units: Subjects
        Female
    543 563 1106
        Male
    1060 1041 2101
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    150 119 269
        Not Hispanic or Latino
    446 477 923
        Unknown or Not Reported
    1007 1008 2015
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    47 41 88
        Asian
    199 205 404
        Native Hawaiian or Other Pacific Islander
    6 7 13
        Black or African American
    79 95 174
        White
    1265 1246 2511
        Multiracial/More than 1 race
    7 10 17
    Glycosylated Hemoglobin (HbA1c) Category
    Units: Subjects
        <8.5 percent (%)
    988 936 1924
        >=8.5%
    615 668 1283
    Smoking Classification
    Units: Subjects
        Never smoked
    667 668 1335
        Current smoker
    330 328 658
        Ex-smoker
    606 608 1214
    Region of Enrollment
    Units: Subjects
        Argentina
    121 121 242
        Australia
    34 35 69
        Bulgaria
    21 22 43
        Canada
    104 107 211
        Croatia
    16 17 33
        Czech Republic
    56 56 112
        Estonia
    13 11 24
        France
    3 4 7
        Germany
    30 30 60
        Hong Kong
    29 29 58
        Hungary
    74 72 146
        Israel
    25 26 51
        Italy
    3 3 6
        Korea, Republic of
    29 27 56
        Latvia
    11 11 22
        Lithuania
    15 15 30
        Malaysia
    30 31 61
        Mexico
    26 26 52
        New Zealand
    20 20 40
        Peru
    18 17 35
        Philippines
    25 24 49
        Poland
    118 118 236
        Romania
    5 4 9
        Russian Federation
    25 23 48
        Slovakia
    31 31 62
        South Africa
    10 10 20
        Taiwan, Province of China
    31 31 62
        Thailand
    29 32 61
        Ukraine
    76 76 152
        United Kingdom
    16 16 32
        United States
    559 559 1118
    Height
    For this outcome measure, number of subjects evaluable were 1598 and 1597 for each arm, respectively.
    Units: centimeter (cm)
        arithmetic mean (standard deviation)
    168.1 ± 9.84 167.6 ± 10.54 -
    Weight
    Units: kilogram (kg)
        arithmetic mean (standard deviation)
    91.14 ± 19.832 91.4 ± 21.319 -
    Body Mass Index (BMI)
    For this outcome measure, number of subjects evaluable were 1598 and 1597 for each arm, respectively.
    Units: kilogram per square meter (kg/m^2)
        arithmetic mean (standard deviation)
    32.14 ± 6.107 32.45 ± 7.497 -
    Duration of Diabetes
    For this outcome measure, number of subjects evaluable were 1602 and 1602 for each arm, respectively.
    Units: years
        arithmetic mean (standard deviation)
    13.583 ± 8.409 13.333 ± 8.321 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Fasiglifam placebo-matching tablet, orally, once daily for up to 588 days.

    Reporting group title
    Fasiglifam 50 mg
    Reporting group description
    Fasiglifam 50 mg, tablet, orally, once daily for up to 582 days.

    Primary: Time to First Occurrence of Any Component of Primary Major Adverse Cardiovascular Event (MACE) Composite

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    End point title
    Time to First Occurrence of Any Component of Primary Major Adverse Cardiovascular Event (MACE) Composite [1]
    End point description
    The time from randomization to the first occurrences of any event in the primary MACE composite was evaluated using Kaplan-Meier analysis. The primary MACE composite comprised cardiovascular (CV) death, nonfatal myocardial infarction (MI), nonfatal stroke, and hospitalization for unstable angina (with or without revascularization). Full Analysis Set (FAS) included all randomized subjects who had baseline and at least 1 post-baseline assessment. Here, '99999' reported for median and 95% confidence interval (CI) signifies not estimable. Median time and corresponding 95% confidence interval could not be reached since very low number of participants (<50%) had event related to any component of primary MACE composite.
    End point type
    Primary
    End point timeframe
    Baseline up to end of study (up to Day 588)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Median time and associated confidence interval could not be reached for any treatment group. Hence, comparative statistics could not be performed.
    End point values
    Placebo Fasiglifam 50 mg
    Number of subjects analysed
    1603
    1604
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to First Occurrence of Any Component of Secondary Major Adverse Cardiovascular Event (MACE) Composite

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    End point title
    Time to First Occurrence of Any Component of Secondary Major Adverse Cardiovascular Event (MACE) Composite
    End point description
    The time from randomization to the first occurrences of any event in the secondary MACE composite was evaluated using Kaplan-Meier analysis. The secondary MACE composite comprised CV death, nonfatal MI, and nonfatal stroke. FAS included all randomized subjects who had baseline and at least 1 post-baseline assessment. Here, '99999' reported for median and 95% CI signifies not estimable. Median time and corresponding 95% confidence interval could not be reached since very low number of participants (<50%) had event related to any component of secondary MACE composite.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of study (up to Day 588)
    End point values
    Placebo Fasiglifam 50 mg
    Number of subjects analysed
    1603
    1604
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 30 days after the last dose of double-blind study drug.
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the subject or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Fasiglifam placebo-matching tablet, orally, once daily for up to 588 days.

    Reporting group title
    Fasiglifam 50 mg
    Reporting group description
    Fasiglifam 50 mg, tablet, orally, once daily for up to 582 days.

    Serious adverse events
    Placebo Fasiglifam 50 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    197 / 1603 (12.29%)
    201 / 1601 (12.55%)
         number of deaths (all causes)
    13
    12
         number of deaths resulting from adverse events
    2
    0
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    2 / 1603 (0.12%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Femoral artery occlusion
         subjects affected / exposed
    0 / 1603 (0.00%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 1603 (0.06%)
    5 / 1601 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 1603 (0.00%)
    3 / 1601 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 1603 (0.12%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 1603 (0.06%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    3 / 1603 (0.19%)
    3 / 1601 (0.19%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous occlusion
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Coronary arterial stent insertion
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary revascularisation
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot amputation
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone cancer metastatic
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer stage IV
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic cancer
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine benign neoplasm
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Malignant melanoma
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic neoplasm
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectosigmoid cancer
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         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
    Chest discomfort
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    6 / 1603 (0.37%)
    8 / 1601 (0.50%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 1603 (0.00%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Local swelling
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device pain
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 1603 (0.19%)
    4 / 1601 (0.25%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Delusion
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychogenic seizure
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    2 / 1603 (0.12%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 1603 (0.06%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postpericardiotomy syndrome
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon injury
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Angiogram
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram ST segment elevation
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    3 / 1603 (0.19%)
    3 / 1601 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    9 / 1603 (0.56%)
    12 / 1601 (0.75%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    7 / 1603 (0.44%)
    9 / 1601 (0.56%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    5 / 1603 (0.31%)
    7 / 1601 (0.44%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 1603 (0.00%)
    3 / 1601 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    4 / 1603 (0.25%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    3 / 1603 (0.19%)
    3 / 1601 (0.19%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 1603 (0.06%)
    4 / 1601 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 4
    Cardiac disorder
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 1603 (0.12%)
    4 / 1601 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    7 / 1603 (0.44%)
    12 / 1601 (0.75%)
         occurrences causally related to treatment / all
    2 / 7
    2 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 1603 (0.12%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    7 / 1603 (0.44%)
    6 / 1601 (0.37%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 1603 (0.00%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    5 / 1603 (0.31%)
    4 / 1601 (0.25%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    4 / 1603 (0.25%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Right ventricular failure
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 1603 (0.06%)
    3 / 1601 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 1603 (0.12%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 1603 (0.00%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 1603 (0.12%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 1603 (0.06%)
    3 / 1601 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid arteriosclerosis
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central pain syndrome
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    7 / 1603 (0.44%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 1603 (0.06%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    5 / 1603 (0.31%)
    3 / 1601 (0.19%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 1603 (0.06%)
    3 / 1601 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 1603 (0.00%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic retinopathy
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 1603 (0.00%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 1603 (0.00%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroduodenitis
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 1603 (0.12%)
    3 / 1601 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 1603 (0.06%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic calcification
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (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
    2 / 1603 (0.12%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 1603 (0.06%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder prolapse
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    4 / 1603 (0.25%)
    6 / 1601 (0.37%)
         occurrences causally related to treatment / all
    2 / 4
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    6 / 1603 (0.37%)
    11 / 1601 (0.69%)
         occurrences causally related to treatment / all
    1 / 6
    3 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure chronic
         subjects affected / exposed
    2 / 1603 (0.12%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal infarct
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 1603 (0.06%)
    3 / 1601 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    2 / 1603 (0.12%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 1603 (0.12%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic mass
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    3 / 1603 (0.19%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nail bed inflammation
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 1603 (0.00%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Pituitary haemorrhage
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (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
    Diabetes mellitus inadequate control
         subjects affected / exposed
    2 / 1603 (0.12%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    2 / 1603 (0.12%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    4 / 1603 (0.25%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    4 / 1603 (0.25%)
    5 / 1601 (0.31%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 1603 (0.06%)
    3 / 1601 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 1603 (0.12%)
    6 / 1601 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic gangrene
         subjects affected / exposed
    1 / 1603 (0.06%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 1603 (0.06%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 1603 (0.06%)
    4 / 1601 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 1603 (0.31%)
    7 / 1601 (0.44%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 1603 (0.12%)
    3 / 1601 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal urinary tract infection
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 1603 (0.00%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 1603 (0.06%)
    2 / 1601 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 1603 (0.06%)
    1 / 1601 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 1603 (0.06%)
    0 / 1601 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Placebo Fasiglifam 50 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    427 / 1603 (26.64%)
    415 / 1601 (25.92%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    40 / 1603 (2.50%)
    42 / 1601 (2.62%)
         occurrences all number
    40
    43
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    30 / 1603 (1.87%)
    40 / 1601 (2.50%)
         occurrences all number
    34
    43
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    26 / 1603 (1.62%)
    33 / 1601 (2.06%)
         occurrences all number
    26
    34
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    30 / 1603 (1.87%)
    39 / 1601 (2.44%)
         occurrences all number
    31
    45
    Headache
         subjects affected / exposed
    32 / 1603 (2.00%)
    41 / 1601 (2.56%)
         occurrences all number
    37
    46
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    48 / 1603 (2.99%)
    44 / 1601 (2.75%)
         occurrences all number
    53
    47
    Nausea
         subjects affected / exposed
    35 / 1603 (2.18%)
    33 / 1601 (2.06%)
         occurrences all number
    37
    34
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    36 / 1603 (2.25%)
    41 / 1601 (2.56%)
         occurrences all number
    37
    43
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    45 / 1603 (2.81%)
    49 / 1601 (3.06%)
         occurrences all number
    51
    53
    Influenza
         subjects affected / exposed
    37 / 1603 (2.31%)
    34 / 1601 (2.12%)
         occurrences all number
    41
    34
    Nasopharyngitis
         subjects affected / exposed
    55 / 1603 (3.43%)
    61 / 1601 (3.81%)
         occurrences all number
    62
    69
    Sinusitis
         subjects affected / exposed
    36 / 1603 (2.25%)
    22 / 1601 (1.37%)
         occurrences all number
    44
    26
    Upper respiratory tract infection
         subjects affected / exposed
    87 / 1603 (5.43%)
    75 / 1601 (4.68%)
         occurrences all number
    107
    85
    Urinary tract infection
         subjects affected / exposed
    43 / 1603 (2.68%)
    35 / 1601 (2.19%)
         occurrences all number
    51
    42

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Mar 2012
    • Clarified that study drug could be temporarily suspended and reinitiated and that subjects who temporarily suspended or permanently discontinued study drug could continue in the study and follow the schedule of study procedures unless they explicitly withdrew consent; and to clarify options for continued study participation that were to be offered to subjects who voluntarily withdrew. • Tests for urine albumin, protein, and creatinine were changed from qualitative to quantitative to allow calculation of albumin/creatinine and protein/creatinine ratios
    13 Nov 2012
    • Indicated which subjects with elevated liver enzyme results or elevated liver enzyme and liver function test (LFT) results should be referred to a hepatologist, based on a recommendation from the German Central Ethics Committee.
    03 Apr 2013
    • Clarified that only abnormal liver enzyme results (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >3 times the upper limit of normal [ULN] in a subject with normal baseline ALT or AST; ALT or AST >5*ULN and 2-fold greater than baseline in a subject with elevated baseline ALT or AST) that occurred on 2 consecutive occasions were to be reported as an adverse event.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Dec 2013
    Following completion of the first phase 3 study (TAK-875_301), and after careful consideration of the data emerging from all the clinical studies and in consultation with the data monitoring committee (DMC), the Liver Safety Evaluation Committee, and the Executive Committee overseeing the fasiglifam CV outcomes trial (TAK-875_306), Takeda concluded that based on all available information, the benefits of treating subjects with fasiglifam do not outweigh the potential risks, thus Takeda decided voluntarily to terminate all development activities for fasiglifam based on liver safety concerns.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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