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    Clinical Trial Results:
    A Double Blind, Randomized, Placebo Controlled, Parallel Group Study to Simultaneously Qualify a Biomarker Algorithm for Prognosis of Risk of Developing Mild Cognitive Impairment due to Alzheimer’s Disease (MCI due to AD) and to Test the Safety and Efficacy of Pioglitazone (AD-4833 SR 0.8 mg QD) to Delay the Onset of MCI due to AD in Cognitively Normal Subjects

    Summary
    EudraCT number
    2012-003111-58
    Trial protocol
    GB   IT   DE  
    Global end of trial date
    06 Sep 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    07 Aug 2019
    First version publication date
    07 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AD-4833/TOMM40_301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01931566
    WHO universal trial number (UTN)
    U1111-1139-0355
    Sponsors
    Sponsor organisation name
    Takeda Development Center Americas, Inc.
    Sponsor organisation address
    One Takeda Parkway, Deerfield, IL, United States, 60015
    Public contact
    Medical Director, Clinical Science, Takeda Development Center Americas, Inc., +1 877-825-3327, clinicaltrialregistry@tpna.com
    Scientific contact
    Medical Director, Clinical Science, Takeda Development Center Americas, Inc., +1 877-825-3327, clinicaltrialregistry@tpna.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
    06 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Sep 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study is to qualify the biomarker risk algorithm composed of TOMM40 rs10524523 genotype, apolipoprotein E (APOE) genotype, and age for prognosis of the risk of developing mild cognitive impairment (MCI) due to Alzheimer’s Disease (AD) within 5 years; and to evaluate the efficacy of pioglitazone compared with placebo to delay the onset of MCI due to AD in cognitively-normal subjects who are at high-risk, as identified by the biomarker risk algorithm at enrollment, for developing MCI due to AD within 5 years.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Aug 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 489
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    Switzerland: 39
    Country: Number of subjects enrolled
    United Kingdom: 728
    Country: Number of subjects enrolled
    United States: 2217
    Worldwide total number of subjects
    3494
    EEA total number of subjects
    749
    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)
    0
    From 65 to 84 years
    3494
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study at 57 investigative sites in United States, United Kingdom, Germany, Australia, and Switzerland from 01 Aug 2013 to 06 Sep 2018.

    Pre-assignment
    Screening details
    Participants with a diagnosis of MCI due to AD were enrolled to receive either pioglitazone (0.8 mg sustained release tablet) or placebo.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Carer, Data analyst, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Low Risk Placebo
    Arm description
    Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to low risk group for developing MCI-AD for up to 5 years.
    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
    Pioglitazone placebo-matching tablets

    Arm title
    High Risk Placebo
    Arm description
    Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.
    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
    Pioglitazone placebo-matching tablets

    Arm title
    High Risk Pioglitazone
    Arm description
    Pioglitazone 0.8 mg, sustained release (SR) tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Pioglitazone
    Investigational medicinal product code
    Other name
    AD-4833
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Pioglitazone tablets

    Number of subjects in period 1
    Low Risk Placebo High Risk Placebo High Risk Pioglitazone
    Started
    433
    1516
    1545
    Treated
    423
    1467
    1491
    Completed
    4
    40
    39
    Not completed
    429
    1476
    1506
         Missing
    -
    -
    1
         Voluntary Withdrawal
    78
    245
    225
         Randomized But Not Treated
    6
    9
    14
         Reason Not Specified
    11
    47
    53
         Major Protocol Deviation
    5
    14
    21
         Study Termination
    289
    968
    1037
         Adverse event, non-fatal
    37
    167
    132
         Lost to follow-up
    3
    26
    23

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Low Risk Placebo
    Reporting group description
    Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to low risk group for developing MCI-AD for up to 5 years.

    Reporting group title
    High Risk Placebo
    Reporting group description
    Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

    Reporting group title
    High Risk Pioglitazone
    Reporting group description
    Pioglitazone 0.8 mg, sustained release (SR) tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

    Reporting group values
    Low Risk Placebo High Risk Placebo High Risk Pioglitazone Total
    Number of subjects
    433 1516 1545 3494
    Age, Customized
    Units: Subjects
        <75 years
    360 632 658 1650
        >=75 years
    73 884 887 1844
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    70.3 ± 4.02 74.6 ± 5.27 74.4 ± 5.25 -
    Sex: Female, Male
    Units: Subjects
        Female
    259 850 812 1921
        Male
    174 666 733 1573
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    8 19 12 39
        Not Hispanic or Latino
    425 1497 1533 3455
        Unknown or Not Reported
    0 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    0 0 4 4
        Asian
    1 10 14 25
        Black or African American
    10 38 39 87
        Native Hawaiian or Other Pacific Islander
    0 1 1 2
        White
    421 1463 1484 3368
        Multiracial
    1 4 3 8
    Race/Ethnicity, Customized
    Units: Subjects
        Non-Hispanic/Latino Caucasian
    413 1444 1472 3329
        Hispanic/Latino and/or non-Caucasian
    20 72 73 165
    Region of Enrollment
    Units: Subjects
        United States|
    270 962 985 2217
        United Kingdom|
    102 311 315 728
        Australia|
    56 215 218 489
        Switzerland|
    3 18 18 39
        Germany|
    2 10 9 21

    End points

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    End points reporting groups
    Reporting group title
    Low Risk Placebo
    Reporting group description
    Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to low risk group for developing MCI-AD for up to 5 years.

    Reporting group title
    High Risk Placebo
    Reporting group description
    Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

    Reporting group title
    High Risk Pioglitazone
    Reporting group description
    Pioglitazone 0.8 mg, sustained release (SR) tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

    Primary: Time to Diagnosis of Mild Cognitive Impairment due to Alzheimer's Disease (MCI-AD) for Placebo-treated, High-risk, Non-Hispanic/Latino Caucasian Participants versus Placebo-treated, Low-risk, Non-Hispanic/Latino Caucasian Participants

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    End point title
    Time to Diagnosis of Mild Cognitive Impairment due to Alzheimer's Disease (MCI-AD) for Placebo-treated, High-risk, Non-Hispanic/Latino Caucasian Participants versus Placebo-treated, Low-risk, Non-Hispanic/Latino Caucasian Participants [1]
    End point description
    The event definition for MCI-AD was the time in days from the randomization date to the date of the first of two consecutive scheduled visits at which a participant was assessed with a diagnosis of MCI due to AD confirmed by adjudication committee. Here, the time to event was reported as the restricted mean survival time. The restricted mean survival time was defined as the area under the curve of the survival function up to the largest event time. Full Analysis Set (FAS) included all participants who were randomized, received at least 1 dose of study drug, and at least 1 valid postbaseline value for assessment of primary efficacy. A participant who did not have an event of MCI due to AD was censored at the date of the last visit at which MCI due to AD could have been assessed.
    End point type
    Primary
    End point timeframe
    Baseline to the end of study (approximately up to 5 years)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned in the participants who received a placebo.
    End point values
    Low Risk Placebo High Risk Placebo
    Number of subjects analysed
    402
    1406
    Units: days
        arithmetic mean (full range (min-max))
    905.44 (189.00 to 909.00)
    1238.67 (168.00 to 1268.00)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Low Risk Placebo v High Risk Placebo
    Number of subjects included in analysis
    1808
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.016 [2]
    Method
    Weighted Generalized Log Rank Test
    Confidence interval
    Notes
    [2] - P-value comparing high risk to low risk placebo was obtained using weighted generalized log-rank test stratified by gender as nonparametric analysis.

    Primary: Time to Diagnosis of MCI due to AD for Pioglitazone-treated, High-risk, Non-Hispanic/Latino Caucasian Participants versus Placebo-treated, High-risk, Non-Hispanic/Latino, Caucasian Participants

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    End point title
    Time to Diagnosis of MCI due to AD for Pioglitazone-treated, High-risk, Non-Hispanic/Latino Caucasian Participants versus Placebo-treated, High-risk, Non-Hispanic/Latino, Caucasian Participants [3]
    End point description
    The event definition for MCI-AD was the time in days from the randomization date to the date of the first of two consecutive scheduled visits at which a participant was assessed with a diagnosis of MCI due to AD confirmed by adjudication committee. Here, the time to event was reported as the restricted mean survival time. The restricted mean survival time was defined as the area under the curve of the survival function up to the largest event time. FAS included all participants who were randomized, received at least 1 dose of study drug, and at least 1 valid postbaseline value for assessment of primary efficacy. A participant who did not have an event of MCI due to AD was censored at the date of the last visit at which MCI due to AD could have been assessed.
    End point type
    Primary
    End point timeframe
    Baseline to the end of study (approximately up to 5 years)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned in the High-risk stratum of participants.
    End point values
    High Risk Placebo High Risk Pioglitazone
    Number of subjects analysed
    1406
    1430
    Units: days
        arithmetic mean (full range (min-max))
    1238.67 (168.00 to 1268.00)
    1261.24 (168.00 to 1285.00)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    High Risk Placebo v High Risk Pioglitazone
    Number of subjects included in analysis
    2836
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.314 [4]
    Method
    Weighted Generalized Log Rank Test
    Confidence interval
    Notes
    [4] - P-value comparing active to placebo was obtained using the weighted generalized log-rank test stratified by gender as a nonparametric analysis.

    Secondary: Change from Baseline for Cognitive Decline on Composite Score on the Cognitive Test Battery for Pioglitazone-treated Participants versus Placebo-treated Participants in the High-risk Stratum

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    End point title
    Change from Baseline for Cognitive Decline on Composite Score on the Cognitive Test Battery for Pioglitazone-treated Participants versus Placebo-treated Participants in the High-risk Stratum [5]
    End point description
    Composite scores derived from the test battery. Domains of Episodic Memory [California Verbal Learning Test-2nd Edition (CVLT-II), Brief Visuospatial Memory Test-Revised (BVMT-R)]; Executive Function [Trail Making Test (TMT) (Part B), Wechsler Adult Intelligence Scale (WAIS)-III Digit Span Test-backwards span]; Language [Multilingual Naming Test (MiNT), Semantic Fluency (animals), Lexical/phonemic fluency (F, A, and S in English; D, S, and F in German)]; and Attention [WAIS-III Digit Span Test-forward span, TMT (Part A)] used for composite score. 12 measures were derived from 8 neuropsychological tests. CVLT-II test involved 2 primary measures (short, long delay recall); BVMT-R had 2 measures (copy and recall); Digit Span and Trail both had 2 measures (forward and backward span and Parts A and B). There was 1 total score for each test: CDT, MINT, semantic and lexical fluency. Total score ranged from -1.222 to 1.707 at baselinbe, a higher composite score indicated better cognition.
    End point type
    Secondary
    End point timeframe
    Baseline and Months 6, 12, 18, 24, 30, 36, 42 and 48
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned in the High-risk stratum of participants.
    End point values
    High Risk Placebo High Risk Pioglitazone
    Number of subjects analysed
    1406
    1430
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change at Month 6|
    0.0186 ± 0.30742
    0.0338 ± 0.29547
        Change at Month 12|
    0.0682 ± 0.30721
    0.0904 ± 0.29531
        Change at Month 18|
    0.0752 ± 0.31077
    0.0892 ± 0.30919
        Change at Month 24|
    0.1005 ± 0.31814
    0.1189 ± 0.30424
        Change at Month 30|
    0.1202 ± 0.33480
    0.1297 ± 0.31836
        Change at Month 36|
    0.1507 ± 0.32076
    0.1436 ± 0.31619
        Change at Month 42|
    0.1501 ± 0.32423
    0.0973 ± 0.32720
        Change at Month 48|
    0.1841 ± 0.27508
    0.1687 ± 0.40621
    No statistical analyses for this end point

    Secondary: Change from Baseline in Instrumental Activities of Daily Living (Alzheimer's Disease Cooperative Study Activities of Daily Living - Prevention Instrument [ADCS ADL-PI]) between Pioglitazone-treated and Placebo-treated Groups of the High-risk Stratum

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    End point title
    Change from Baseline in Instrumental Activities of Daily Living (Alzheimer's Disease Cooperative Study Activities of Daily Living - Prevention Instrument [ADCS ADL-PI]) between Pioglitazone-treated and Placebo-treated Groups of the High-risk Stratum [6]
    End point description
    The ADCS ADL-PI is a functional measure that was specifically designed for standardized administration over long duration clinical studies to prevent AD. The ADCS ADL-PI is a 20-item instrument that included 15 ADL questions, which were scored as 1 (with a lot of difficulty), 2 (with some difficulty), or 3 (as well as usually, with no difficulty), plus 5 vision, hearing, and mobility questions, which were scored from 0 (no) to 1 (yes). ADL Total ranged from 0 to 45, and lower scores indicated greater disability. Full Analysis Set (FAS) included all participants who were randomized, received at least 1 dose of study drug, and at least 1 valid postbaseline value for assessment of primary efficacy. A participant who does not have an event of MCI due to AD was censored at the date of the last visit at which MCI due to AD could have been assessed.
    End point type
    Secondary
    End point timeframe
    Baseline and Months 6, 12, 18, 24, 30, 36, 42 and 48
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned in the High-risk stratum of participants.
    End point values
    High Risk Placebo High Risk Pioglitazone
    Number of subjects analysed
    1406
    1430
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change at Month 6|
    0.1 ± 3.54
    0.1 ± 3.50
        Change at Month 12|
    0.0 ± 3.99
    0.1 ± 3.95
        Change at Month 18|
    0.1 ± 3.87
    0.2 ± 3.59
        Change at Month 24|
    0.3 ± 3.78
    0.2 ± 3.63
        Change at Month 30|
    0.3 ± 3.76
    0.1 ± 3.61
        Change at Month 36|
    0.2 ± 3.77
    0.2 ± 3.72
        Change at Month 42|
    0.3 ± 3.63
    0.3 ± 3.74
        Change at Month 48|
    0.1 ± 4.93
    0.3 ± 5.32
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 30 days after the last dose of study drug (up to 935 days)
    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 participant 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
    21.0
    Reporting groups
    Reporting group title
    Low Risk Placebo
    Reporting group description
    Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to low risk group for developing MCI-AD for up to 5 years.

    Reporting group title
    High Risk Placebo
    Reporting group description
    Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

    Reporting group title
    High Risk Pioglitazone
    Reporting group description
    Pioglitazone 0.8 mg, sustained release (SR) tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

    Serious adverse events
    Low Risk Placebo High Risk Placebo High Risk Pioglitazone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    81 / 427 (18.97%)
    404 / 1507 (26.81%)
    358 / 1531 (23.38%)
         number of deaths (all causes)
    2
    21
    7
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 427 (0.23%)
    7 / 1507 (0.46%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 427 (0.47%)
    7 / 1507 (0.46%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    4 / 1507 (0.27%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    3 / 1507 (0.20%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
    Additional description: Two treatment-emergent deaths occurred during treatment with placebo (in high-risk group) and were not related.
         subjects affected / exposed
    0 / 427 (0.00%)
    4 / 1507 (0.27%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 427 (0.23%)
    3 / 1507 (0.20%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 427 (0.00%)
    3 / 1507 (0.20%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 427 (0.23%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periprosthetic osteolysis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention postoperative
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Avulsion fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract operation complication
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Flatback syndrome
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fractured ischium
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative respiratory failure
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural intestinal perforation
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural vomiting
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stress fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haemorrhage
    Additional description: One treatment-emergent death occurred in participant who also suffered from cerebrovascular accident during treatment with placebo (in high-risk group) and was not related.
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Tendon injury
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound secretion
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood magnesium decreased
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood parathyroid hormone increased
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heart rate irregular
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    5 / 427 (1.17%)
    15 / 1507 (1.00%)
    16 / 1531 (1.05%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 20
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    3 / 427 (0.70%)
    10 / 1507 (0.66%)
    6 / 1531 (0.39%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 10
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 427 (0.47%)
    7 / 1507 (0.46%)
    7 / 1531 (0.46%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
    Additional description: Four treatment-emergent deaths occurred during treatment with placebo (in high-risk group) and were not related.
         subjects affected / exposed
    0 / 427 (0.00%)
    13 / 1507 (0.86%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 13
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    Cardiac failure congestive
    Additional description: Two treatment-emergent deaths occurred during treatment with placebo (in high-risk group) and were not related.
         subjects affected / exposed
    1 / 427 (0.23%)
    8 / 1507 (0.53%)
    6 / 1531 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 11
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Acute myocardial infarction
    Additional description: One treatment-emergent death occurred during treatment with pioglitazone (in high-risk group) and was not related.
         subjects affected / exposed
    1 / 427 (0.23%)
    5 / 1507 (0.33%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sinus node dysfunction
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    5 / 1531 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 427 (0.00%)
    4 / 1507 (0.27%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    5 / 1531 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
    Additional description: Two treatment-emergent deaths occurred during treatment with placebo (in high-risk group) and were not related.
         subjects affected / exposed
    0 / 427 (0.00%)
    3 / 1507 (0.20%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 427 (0.23%)
    3 / 1507 (0.20%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 427 (0.23%)
    1 / 1507 (0.07%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 427 (0.23%)
    2 / 1507 (0.13%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 427 (0.00%)
    3 / 1507 (0.20%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
    Additional description: One treatment-emergent death occurred during treatment with pioglitazone (in high-risk group) and was not related.
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Aortic valve stenosis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extrasystoles
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriospasm coronary
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial septal defect acquired
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve disease
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital cerebrovascular anomaly
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 427 (0.00%)
    3 / 1507 (0.20%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    2 / 427 (0.47%)
    13 / 1507 (0.86%)
    14 / 1531 (0.91%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 13
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 427 (0.00%)
    11 / 1507 (0.73%)
    10 / 1531 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 11
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
    Additional description: One treatment-emergent death occurred in participant who also suffered from subdural haemorrhage during treatment with placebo (in high-risk group) and was not related.
         subjects affected / exposed
    1 / 427 (0.23%)
    10 / 1507 (0.66%)
    6 / 1531 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 10
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 427 (0.23%)
    4 / 1507 (0.27%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 427 (0.00%)
    3 / 1507 (0.20%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
    Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was not related.
         subjects affected / exposed
    0 / 427 (0.00%)
    3 / 1507 (0.20%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 427 (0.23%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 427 (0.23%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient global amnesia
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Amnesia
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness postural
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial neuralgia
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
    Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was not related.
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    IIIrd nerve paralysis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lacunar stroke
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nerve compression
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Temporal lobe epilepsy
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Macular fibrosis
         subjects affected / exposed
    2 / 427 (0.47%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dacryostenosis acquired
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular oedema
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neovascular age-related macular degeneration
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 427 (0.23%)
    1 / 1507 (0.07%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    1 / 427 (0.23%)
    3 / 1507 (0.20%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    0 / 427 (0.00%)
    8 / 1507 (0.53%)
    5 / 1531 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    5 / 1531 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    4 / 1531 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 427 (0.00%)
    3 / 1507 (0.20%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 427 (0.00%)
    3 / 1507 (0.20%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    1 / 427 (0.23%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 427 (0.23%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal adhesions
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Functional gastrointestinal disorder
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gallstone ileus
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal pseudo-obstruction
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal spasm
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 427 (0.70%)
    5 / 1507 (0.33%)
    7 / 1531 (0.46%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 427 (0.23%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic nephropathy
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower urinary tract symptoms
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral obstruction
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinoma
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Precancerous skin lesion
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    4 / 427 (0.94%)
    22 / 1507 (1.46%)
    23 / 1531 (1.50%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 24
    0 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    3 / 427 (0.70%)
    13 / 1507 (0.86%)
    10 / 1531 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 14
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 427 (0.23%)
    6 / 1507 (0.40%)
    8 / 1531 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 427 (0.47%)
    4 / 1507 (0.27%)
    5 / 1531 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    4 / 1531 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 427 (0.23%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 427 (0.23%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dupuytren's contracture
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture pain
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint instability
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myosclerosis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in jaw
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sacroiliitis
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Scoliosis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seronegative arthritis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon disorder
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertebral foraminal stenosis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertebral osteophyte
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Thyroid mass
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 427 (0.23%)
    3 / 1507 (0.20%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral salt-wasting syndrome
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
    Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was not related.
         subjects affected / exposed
    3 / 427 (0.70%)
    12 / 1507 (0.80%)
    15 / 1531 (0.98%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 13
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Diverticulitis
         subjects affected / exposed
    3 / 427 (0.70%)
    7 / 1507 (0.46%)
    4 / 1531 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 427 (0.23%)
    3 / 1507 (0.20%)
    8 / 1531 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 427 (0.23%)
    5 / 1507 (0.33%)
    6 / 1531 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 427 (0.47%)
    4 / 1507 (0.27%)
    4 / 1531 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 427 (0.23%)
    5 / 1507 (0.33%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 427 (0.47%)
    1 / 1507 (0.07%)
    4 / 1531 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 427 (0.00%)
    3 / 1507 (0.20%)
    4 / 1531 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 427 (0.23%)
    2 / 1507 (0.13%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 427 (0.00%)
    4 / 1507 (0.27%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 427 (0.23%)
    2 / 1507 (0.13%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coccidioidomycosis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningoencephalitis herpetic
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural cellulitis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 427 (0.23%)
    3 / 1507 (0.20%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
    Additional description: One treatment-emergent death occurred during treatment with placebo (in low-risk group) and was not related.
         subjects affected / exposed
    1 / 427 (0.23%)
    4 / 1507 (0.27%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 427 (0.00%)
    3 / 1507 (0.20%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior mesenteric artery syndrome
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Shoulder arthroplasty
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    1 / 427 (0.23%)
    8 / 1507 (0.53%)
    5 / 1531 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    2 / 427 (0.47%)
    2 / 1507 (0.13%)
    4 / 1531 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
    Additional description: One treatment-emergent death occurred during treatment with placebo (in low-risk group) and was not related. Two treatment-emergent deaths occurred during treatment with placebo (in high-risk group) and were not related.
         subjects affected / exposed
    1 / 427 (0.23%)
    3 / 1507 (0.20%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    4 / 1531 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 427 (0.23%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 427 (0.23%)
    2 / 1507 (0.13%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    2 / 427 (0.47%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parathyroid tumour benign
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
    Additional description: One treatment-emergent death occurred during treatment with pioglitazone (in high-risk group) and was not related.
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Anal squamous cell carcinoma
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign renal neoplasm
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer stage 0, with cancer in situ
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer in situ
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac myxoma
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangiocarcinoma
    Additional description: One treatment-emergent death occurred during treatment with pioglitazone (in high-risk group) and was not related.
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Choroid plexus papilloma
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer stage II
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Follicular thyroid cancer
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal carcinoma
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glioma
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial meningioma malignant
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive papillary breast carcinoma
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine benign neoplasm
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma stage II
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
    Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was not related.
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Lung carcinoma cell type unspecified stage IV
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mantle cell lymphoma recurrent
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucinous breast carcinoma
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer stage IIIB
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
    Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was not related.
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Oesophageal carcinoma
    Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was related.
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Oesophageal squamous cell carcinoma
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Papillary cystadenoma lymphomatosum
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Penile squamous cell carcinoma
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Plasmacytoma
    Additional description: One treatment-emergent death occurred during treatment with pioglitazone (in high-risk group) and was not related.
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Polycythaemia vera
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Schwannoma
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord neoplasm
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsil cancer
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 427 (0.23%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 427 (0.00%)
    5 / 1507 (0.33%)
    8 / 1531 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adverse drug reaction
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
    Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was not related.
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ill-defined disorder
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Unevaluable event
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alcohol abuse
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    2 / 427 (0.47%)
    4 / 1507 (0.27%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatomegaly
         subjects affected / exposed
    1 / 427 (0.23%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acquired hydrocele
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatic haemorrhage
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterovaginal prolapse
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 427 (0.23%)
    9 / 1507 (0.60%)
    11 / 1531 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 9
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    2 / 427 (0.47%)
    6 / 1507 (0.40%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 427 (0.00%)
    4 / 1507 (0.27%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 427 (0.23%)
    2 / 1507 (0.13%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
    Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was not related.
         subjects affected / exposed
    1 / 427 (0.23%)
    1 / 1507 (0.07%)
    4 / 1531 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 427 (0.23%)
    3 / 1507 (0.20%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 427 (0.00%)
    3 / 1507 (0.20%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
    Additional description: One treatment-emergent death occurred during treatment with pioglitazone (in high-risk group) and was not related.
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    2 / 1531 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 427 (0.00%)
    2 / 1507 (0.13%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
    Additional description: One treatment-emergent death occurred during treatment with pioglitazone (in high-risk group) and was not related.
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Interstitial lung disease
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary granuloma
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 427 (0.23%)
    3 / 1507 (0.20%)
    6 / 1531 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 427 (0.00%)
    3 / 1507 (0.20%)
    3 / 1531 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 427 (0.47%)
    2 / 1507 (0.13%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 427 (0.00%)
    0 / 1507 (0.00%)
    1 / 1531 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Primary biliary cholangitis
         subjects affected / exposed
    0 / 427 (0.00%)
    1 / 1507 (0.07%)
    0 / 1531 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Low Risk Placebo High Risk Placebo High Risk Pioglitazone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    235 / 427 (55.04%)
    828 / 1507 (54.94%)
    822 / 1531 (53.69%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 427 (6.09%)
    97 / 1507 (6.44%)
    93 / 1531 (6.07%)
         occurrences all number
    26
    100
    94
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    18 / 427 (4.22%)
    143 / 1507 (9.49%)
    135 / 1531 (8.82%)
         occurrences all number
    24
    171
    176
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    23 / 427 (5.39%)
    59 / 1507 (3.92%)
    71 / 1531 (4.64%)
         occurrences all number
    27
    74
    89
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 427 (4.68%)
    79 / 1507 (5.24%)
    76 / 1531 (4.96%)
         occurrences all number
    23
    88
    87
    Eye disorders
    Cataract
         subjects affected / exposed
    27 / 427 (6.32%)
    119 / 1507 (7.90%)
    106 / 1531 (6.92%)
         occurrences all number
    33
    159
    149
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    24 / 427 (5.62%)
    70 / 1507 (4.64%)
    72 / 1531 (4.70%)
         occurrences all number
    24
    75
    75
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    45 / 427 (10.54%)
    125 / 1507 (8.29%)
    125 / 1531 (8.16%)
         occurrences all number
    54
    145
    148
    Back pain
         subjects affected / exposed
    31 / 427 (7.26%)
    82 / 1507 (5.44%)
    101 / 1531 (6.60%)
         occurrences all number
    32
    89
    109
    Osteoarthritis
         subjects affected / exposed
    19 / 427 (4.45%)
    81 / 1507 (5.37%)
    86 / 1531 (5.62%)
         occurrences all number
    22
    90
    95
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    62 / 427 (14.52%)
    190 / 1507 (12.61%)
    183 / 1531 (11.95%)
         occurrences all number
    85
    255
    239
    Urinary tract infection
         subjects affected / exposed
    47 / 427 (11.01%)
    178 / 1507 (11.81%)
    191 / 1531 (12.48%)
         occurrences all number
    78
    305
    302
    Nasopharyngitis
         subjects affected / exposed
    22 / 427 (5.15%)
    72 / 1507 (4.78%)
    90 / 1531 (5.88%)
         occurrences all number
    24
    88
    106
    Sinusitis
         subjects affected / exposed
    22 / 427 (5.15%)
    67 / 1507 (4.45%)
    52 / 1531 (3.40%)
         occurrences all number
    27
    83
    62

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Apr 2013
    The following changes were made as per Amendment 1: Modified the order of the cognitive test battery. Changed the Informed Consent for Project Partner to a Project Partner Acknowledgement Form. Modified the randomization in an amyloid-related imaging abnormalities (ARIA) substudy.
    19 Mar 2014
    The following changes were made as per Amendment 2: Changed the timing of the ad hoc magnetic resonance imaging (MRI) done in conjunction with MCI due to AD diagnosis from the first of the 2 consecutive visits to the end of the second Comprehensive Medical Follow-Up Visit. Deleted an inclusion criterion regarding the requirement for vitamin D and calcium. Corrected the description of mandatory risk stratification genetic sample processing. Changed the ARIA substudy to a substudy focused on volumetric MRI changes, and removed ARIA from the list of adverse events of special interest (AESIs).
    10 Nov 2014
    The following changes were made as per Amendment 3: Provided sites with an option to consent subjects with a full study informed consent at Visit 1 or a split Screening informed consent at Visit 1 (Screening) and a Study entry informed consent at Visit 2 (Baseline). Extended the visit window for screening to randomization, to provide additional flexibility in scheduling Baseline and Randomization Visits if needed, once risk stratification sample results were obtained from Screening Visit and cognitive battery test results were obtained from Baseline Visit. Provided the option for sites to include subject consent to pharmacogenomics (PGx) research within the main study informed consent form. Replaced the health care resource utilization (HCRU) instrument with the Alzheimer’s Disease Cooperative Study—Resource Use Inventory (ADCS-RUI) and updated the schedule of this assessment. Permitted sites to perform the screening visit at a subject’s home, after review and approval by the sponsor of the site’s procedures, to provide additional flexibility for scheduling and subject comfort. Permitted sites to administer the Clinical Dementia Rating (CDR) assessment prior to the cognitive battery only during the Baseline Visit, and to administer the Alzheimer’s Disease Cooperative Study—Clinical Global Impression of Change—Mild Cognitive Impairment (ADCS-CGIC-MCI) in parallel with the other cognitive assessments. Reduced the Short Form-36 (SF-36) and European Quality of Life (EQ-5D) assessment schedule.
    24 Jul 2015
    The following changes were made as per Amendment 5: Revised treatment effect size assumption. Removed Russia and Italy as countries for site participation. Corrected exclusion criteria numbers 9 and14. Updated excluded medications table to clarify the exclusion of treatment for Parkinson disease. Updated the assessor expectations for the ADCS-RUI assessment.
    27 Sep 2016
    The following changes were made as per Amendment 6: Revised the efficacy futility analysis to occur once 33% of events had accrued, rather than at 50%. Added an operational futility analysis to enable an assessment of whether the study could feasibly be completed within an acceptable timeframe, based on the accrual rate of adjudicated cases meeting the event definition. Clarified the timing of required MRI scans and removed the requirement to perform an MRI scan if a scan was performed for the study within the preceding 6 months. Introduced additional options for the performance of the Comprehensive Medical Follow-Up Visit, including the ability to perform assessments during routine Month 6 or Month 12 visits in certain situations and during home visits or by telephone (for project partners) in exceptional circumstances. Made microscopic urine screens standard on all urine sample collections at routine visits rather than as a reflex in the event of abnormalities detected on macroscopic examination. Introduced formal limits for assessment of compliance with study drug to help facilitate consistency in global monitoring and reporting of subjects that were not compliant with administration of study drug. Clarified AESI follow-up and reporting of macular degeneration and hypoglycemia to ensure consistency in follow-up of macular edema and to eliminate ambiguity over reporting of hypoglycemia as an AESI, ensuring consistency across all subjects.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    07 Aug 2018
    Terminated due to lack of efficacy of the drug and had no safety concern.
    -

    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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