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    Clinical Trial Results:
    A PHASE 3 STUDY EVALUATING THE EFFECT OF PITAVASTATIN TO PREVENT CARDIOVASCULAR EVENTS IN HIV-1 INFECTED INDIVIDUALS

    Summary
    EudraCT number
    		 2018-001285-41
    Trial protocol
    		 ES  
    Global end of trial date
    21 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Nov 2024
    First version publication date
    09 Nov 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EU5332
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02344290
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND Number: 119127, Secondary Protocol ID: EU5332
    Sponsors
    Sponsor organisation name
    NEAT ID Foundation
    Sponsor organisation address
    CHU Saint Pierre - PL 709 Rue Haute 322, Brussels, Belgium,
    Public contact
    Carl Fletcher, Neat ID Foundation, 0044 7494795982, selina.piper-b@rokcservices.com
    Scientific contact
    Carl Fletcher, Neat ID Foundation, 0044 7494795982, selina.piper-b@rokcservices.com
    Sponsor organisation name
    Massachusetts General Hospital
    Sponsor organisation address
    50 Staniford Street, Boston, MA , United States,
    Public contact
    REPRIEVE Project Manager, REPRIEVE Clinical Coordinating Center, 001 6177249109, mghreprievetrial@mgb.org
    Scientific contact
    REPRIEVE Project Manager, REPRIEVE Clinical Coordinating Center, 001 6177249109, mghreprievetrial@mgb.org
    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
    21 Aug 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Aug 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the effects of pitavastatin as a primary prevention strategy for major adverse cardiovascular events (MACE) in HIV.
    Protection of trial subjects
    The REPRIEVE protocol and the informed consent and any subsequent modifications were reviewed and approved by the IRB/EC responsible for oversight of the study. A signed consent form as obtained from the participant (or legal representative). The consent form described the purpose of the study, the procedures to be followed, and the risks and benefits of participation. A copy of the consent form was given to the participant or legal representative, and retained in the participant’s record. Risks, including potential risks of pitavastatin, and protection against risk were described in the informed consent form. All laboratory specimens, evaluation forms, reports, and other records that left the sites were identified by coded number only to maintain participant confidentiality. All records were kept locked. All computer entry and networking programs was done with coded numbers only. Clinical information will not be released without written permission of the participant, except as necessary for monitoring by the ACTG, IRB/EC, FDA, NHLBI, NIAID, OHRP, and other local, US, and international regulatory entities as part of their duties, or the industry supporters or designee. An independent DSMB empanelled by the NHLBI was responsible for oversight of the trial with respect to safety. The DSMB met every 6-9 months between 2015 and 2023
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Mar 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 213
    Country: Number of subjects enrolled
    Haiti: 140
    Country: Number of subjects enrolled
    United States: 3787
    Country: Number of subjects enrolled
    Thailand: 590
    Country: Number of subjects enrolled
    India: 504
    Country: Number of subjects enrolled
    Canada: 131
    Country: Number of subjects enrolled
    Botswana: 281
    Country: Number of subjects enrolled
    Brazil: 1099
    Country: Number of subjects enrolled
    South Africa: 570
    Country: Number of subjects enrolled
    Uganda: 181
    Country: Number of subjects enrolled
    Zimbabwe: 125
    Country: Number of subjects enrolled
    Peru: 148
    Worldwide total number of subjects
    7769
    EEA total number of subjects
    213
    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)
    7624
    From 65 to 84 years
    145
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants living with HIV who were at risk of cardiovascular disease were randomly assigned to receive 4 mg of pitavastatin or placebo once a day for their entire study duration.

    Pre-assignment
    Screening details
    		 This study enrolled PWH who were on any ART regimen (ART was not provided by the study) for at least 6 months before study entry and were at low to moderate risk of CVD using the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline thresholds for recommended statin initiation.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pitavastatin
    Arm description
    		 Participants received pitavastatin once a day for the entire time they were in study follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pitavastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet (4 mg) taken once daily, orally with or without food

    Arm title
    		 Placebo
    Arm description
    		 Participants were randomly assigned to receive placebo tablet once a day for their entire study duration.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet taken once daily, orally with or without food

    Number of subjects in period 1
    		Pitavastatin Placebo
    Started
    3888
    3881
    Completed
    3201
    3201
    Not completed
    687
    680
         Consent withdrawn by subject
    315
    324
         Physician decision
    25
    25
         Lost to follow-up
    258
    249
         Unable to attend clinic
    69
    60
         Site closure
    15
    19
         not specified
    5
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pitavastatin
    Reporting group description
    		 Participants received pitavastatin once a day for the entire time they were in study follow-up.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomly assigned to receive placebo tablet once a day for their entire study duration.

    Reporting group values
    		 Pitavastatin Placebo Total
    Number of subjects
    		 3888 3881 7769
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 50 (45 to 55) 50 (45 to 55) -
    Gender categorical
    Units: Subjects
        Female
    		 1211 1208 2419
        Male
    		 2677 2673 5350
    Race/Ethnicity
    Race was reported by the participants. “Other” race includes participants who identified as native or indigenous to the enrolment region, as having more than one race, or as having an unknown race.
    Units: Subjects
        Black
    		 1569 1639 3208
        White
    		 1364 1340 2704
        Asian
    		 571 567 1138
        Other
    		 384 335 719
    Global burden of disease
    Units: Subjects
        High Income
    		 2044 2051 4095
        Latin America and Caribbean
    		 709 714 1423
        Southeast or East Asia
    		 304 286 590
        South Asia
    		 246 258 504
        Sub-Saharan Africa
    		 585 572 1157
    Atherosclerotic Cardiovascular Disease (ASCVD) risk score
    10-Year Atherosclerotic Cardiovascular Disease (ASCVD) risk score is calculated based on age, sex, race, systolic blood pressure, total and high-density lipoprotein cholesterol, hypertension treatment, smoking history and presence of diabetes. It is measured on a continuous scale, with 0-<5% considered low risk, 5-<7.5% borderline risk, 7.5-<20% intermediate risk, and ≥20% high risk according to the American College of Cardiology and American Heart Association. More granular categories were used to describe REPRIEVE participants, given the eligibility criterion of low to moderate CVD risk.
    Units: Subjects
        0 - <2.5%
    		 1096 1060 2156
        2.5 - <5%
    		 1030 1025 2055
        5 - <7.5%
    		 934 960 1894
        7.5 - 10%
    		 540 561 1101
        ≥10%
    		 288 275 563
    Nadir CD4 cell count
    Units: Subjects
        <200 cells/mm^3
    		 1890 1911 3801
        200 - 349 cells/mm^3
    		 1019 1022 2041
        ≥350 cells/mm^3
    		 839 825 1664
        Unknown
    		 140 123 263
    CD4 cell count
    Units: Subjects
        ≤500 cells/mm^3
    		 1257 1253 2510
        >500 cells/mm^3
    		 2631 2628 5259
    HIV-1 RNA
    The assays that were used for testing varied, including assays with a lower limit of quantification (LLQ) of 20 to 400 copies/mL
    Units: Subjects
        <LLQ
    		 2641 2609 5250
        LLQ - <400 copies/mL
    		 305 312 617
        ≥400 copies/mL
    		 63 67 130
        Not available
    		 879 893 1772
    Pre-existing diabetes
    Units: Subjects
        Condition present
    		 24 14 38
        Condition absent
    		 3864 3867 7731
    Subject analysis sets

    Subject analysis set title
    All randomised participants
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All participants enrolled according to the randomized treatment group

    Subject analysis sets values
    		 All randomised participants
    Number of subjects
    7769
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    Gender categorical
    Units: Subjects
        Female
        Male
    Race/Ethnicity
    Race was reported by the participants. “Other” race includes participants who identified as native or indigenous to the enrolment region, as having more than one race, or as having an unknown race.
    Units: Subjects
        Black
        White
        Asian
        Other
    Global burden of disease
    Units: Subjects
        High Income
        Latin America and Caribbean
        Southeast or East Asia
        South Asia
        Sub-Saharan Africa
    Atherosclerotic Cardiovascular Disease (ASCVD) risk score
    10-Year Atherosclerotic Cardiovascular Disease (ASCVD) risk score is calculated based on age, sex, race, systolic blood pressure, total and high-density lipoprotein cholesterol, hypertension treatment, smoking history and presence of diabetes. It is measured on a continuous scale, with 0-<5% considered low risk, 5-<7.5% borderline risk, 7.5-<20% intermediate risk, and ≥20% high risk according to the American College of Cardiology and American Heart Association. More granular categories were used to describe REPRIEVE participants, given the eligibility criterion of low to moderate CVD risk.
    Units: Subjects
        0 - <2.5%
        2.5 - <5%
        5 - <7.5%
        7.5 - 10%
        ≥10%
    Nadir CD4 cell count
    Units: Subjects
        <200 cells/mm^3
        200 - 349 cells/mm^3
        ≥350 cells/mm^3
        Unknown
    CD4 cell count
    Units: Subjects
        ≤500 cells/mm^3
        >500 cells/mm^3
    HIV-1 RNA
    The assays that were used for testing varied, including assays with a lower limit of quantification (LLQ) of 20 to 400 copies/mL
    Units: Subjects
        <LLQ
        LLQ - <400 copies/mL
        ≥400 copies/mL
        Not available
    Pre-existing diabetes
    Units: Subjects
        Condition present
    38
        Condition absent
    7731

    End points

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    End points reporting groups
    Reporting group title
    Pitavastatin
    Reporting group description
    		 Participants received pitavastatin once a day for the entire time they were in study follow-up.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomly assigned to receive placebo tablet once a day for their entire study duration.

    Subject analysis set title
    All randomised participants
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All participants enrolled according to the randomized treatment group

    Primary: Incidence Rate of Major Adverse Cardiovascular Event (MACE)

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    End point title
    		 Incidence Rate of Major Adverse Cardiovascular Event (MACE)
    End point description
    End point type
    Primary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrolment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    4.95 (4.07 to 6.03)
    7.77 (6.64 to 9.08)
    Statistical analysis title
    		 Incidence Rate of MACE
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 0.84
    Notes
    [1] - Hazard ratio is shown as pitavastatin/placebo. Two-sided 95% repeated confidence interval that adjusts for interim looks according to the realized Lan and DeMets implementation of the O’Brien-Fleming sequential stopping boundary is presented.

    Secondary: Incidence Rate of Cardiac Ischemia or Myocardial Infarction

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    End point title
    		 Incidence Rate of Cardiac Ischemia or Myocardial Infarction
    End point description
    Cardiac ischemia or myocardial infarction component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrolment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    1.48 (1.03 to 2.11)
    2.65 (2.03 to 3.46)
    Statistical analysis title
    		 Incidence Rate of Cardiac Ischemia
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.87

    Secondary: Incidence Rate of Cerebrovascular Event (Stroke or TIA)

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    End point title
    		 Incidence Rate of Cerebrovascular Event (Stroke or TIA)
    End point description
    Cerebrovascular event (stroke or TIA) component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    1.53 (1.07 to 2.17)
    2.46 (1.86 to 3.24)
    Statistical analysis title
    		 Incidence Rate of Cerebrovascular Event
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.97

    Secondary: Incidence Rate of Peripheral Arterial Ischemia

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    End point title
    		 Incidence Rate of Peripheral Arterial Ischemia
    End point description
    Peripheral arterial ischemia component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    0.10 (0.02 to 0.39)
    0.15 (0.05 to 0.45)
    Statistical analysis title
    		 Incidence Rate of Peripheral Arterial Ischemia
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 4.02

    Secondary: Incidence Rate of Death From CV Causes

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    End point title
    		 Incidence Rate of Death From CV Causes
    End point description
    CV death component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Non-CV deaths and deaths from undetermined causes were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    0.69 (0.41 to 1.16)
    0.98 (0.63 to 1.51)
    Statistical analysis title
    		 Analysis 1 Incidence Rate of Death From CV Causes
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 1.38

    Secondary: Incidence Rate of Death From CV or Undetermined Causes

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    End point title
    		 Incidence Rate of Death From CV or Undetermined Causes
    End point description
    CV or undetermined death component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Non-CV deaths were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    1.72 (1.23 to 2.39)
    2.54 (1.94 to 3.33)
    Statistical analysis title
    		 Statistical Analysis 1 for Incidence Rate of Death
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 1.03

    Secondary: Incidence Rate of Cardiac Catheterization or Revascularization

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    End point title
    		 Incidence Rate of Cardiac Catheterization or Revascularization
    End point description
    Cardiac catheterization or revascularization component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    1.08 (0.71 to 1.64)
    1.77 (1.27 to 2.45)
    Statistical analysis title
    		 Statistical Analysis 1 for Incidence Rate of CC
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 1.05

    Secondary: Incidence Rate of Carotid or Cerebrovascular Revascularization

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    End point title
    		 Incidence Rate of Carotid or Cerebrovascular Revascularization
    End point description
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Incidence Rate of MACE or Death

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    End point title
    		 Incidence Rate of MACE or Death
    End point description
    A composite outcome including MACE and death from any cause. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrolment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    9.31 (8.07 to 10.75)
    12.02 (10.60 to 13.63)
    Statistical analysis title
    		 Statistical Analysis 1 for Incidence Rate of MACE
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 0.94

    Secondary: Incidence Rate of Death (All-cause)

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    End point title
    		 Incidence Rate of Death (All-cause)
    End point description
    Death from any cause. The incidence rates were estimated based on time to event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrolment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    6.18 (5.19 to 7.36)
    6.99 (5.93 to 8.23)
    Statistical analysis title
    		 Statistical Analysis 1 for Incidence Rate of Death
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.12

    Secondary: Incidence Rate of Non-CV Clinical Diagnoses

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    End point title
    		 Incidence Rate of Non-CV Clinical Diagnoses
    End point description
    A composite of non-CV clinical diagnoses including: non-AIDS-defining cancers (excluding basal cell and squamous cell carcinomas of the skin), AIDS-defining events (based on Centers for Disease Control and Prevention [CDC] 2014 classification), end-stage renal disease, and end-stage liver disease. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrolment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    9.17 (7.93 to 10.59)
    9.90 (8.61 to 11.38)
    Statistical analysis title
    		 Statistical Analysis 1 for Incidence Rate
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.13

    Secondary: Incidence Rate of Non-AIDS-defining Cancer

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    End point title
    		 Incidence Rate of Non-AIDS-defining Cancer
    End point description
    Non-AIDS-defining cancer (excluding basal cell and squamous cell carcinomas of the skin) component of the composite non-CV clinical diagnoses outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrolment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    5.25 (4.34 to 6.36)
    5.68 (4.74 to 6.83)
    Statistical analysis title
    		 Statistical Analysis for Non-AIDS-defining Cancer
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.2

    Secondary: Incidence Rate of Peripheral Arterial Revascularization

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    End point title
    		 Incidence Rate of Peripheral Arterial Revascularization
    End point description
    Peripheral arterial revascularization component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrolment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    0 (0 to 0)
    0.29 (0.13 to 0.65)
    Statistical analysis title
    		 Statistical Analysis for Peripheral Arterial
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.54

    Secondary: Incidence Rate of AIDS-defining Event

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    End point title
    		 Incidence Rate of AIDS-defining Event
    End point description
    AIDS-defining event component of the composite non-CV clinical diagnoses outcome. Events were captured based on the Centers for Disease Control and Prevention [CDC] 2014 classification. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    3.36 (2.65 to 4.27)
    3.55 (2.82 to 4.47)
    Statistical analysis title
    		 Statistical Analysis 1 of AIDS-defining Event
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.31

    Secondary: Incidence Rate of End-Stage Renal Disease

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    End point title
    		 Incidence Rate of End-Stage Renal Disease
    End point description
    End-stage renal disease (defined as initiation of dialysis or renal transplantation) component of the composite non-CV clinical diagnoses outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    0.15 (0.05 to 0.46)
    0.24 (0.10 to 0.59)
    Statistical analysis title
    		 Statistical Analysis for End-Stage Renal Disease
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 2.51

    Secondary: Incidence Rate of End-Stage Liver Disease

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    End point title
    		 Incidence Rate of End-Stage Liver Disease
    End point description
    End-stage liver disease (defined as cirrhosis or hepatic decompensation requiring hospitalization) component of the composite non-CV clinical diagnoses outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 1000 person-years
        number (confidence interval 95%)
    0.59 (0.33 to 1.04)
    0.64 (0.37 to 1.10)
    Statistical analysis title
    		 Statistical Analysis 1 for End-Stage Liver Disease
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 2.02

    Secondary: Incidence Rate of Non-fatal Serious Adverse Event

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    End point title
    		 Incidence Rate of Non-fatal Serious Adverse Event
    End point description
    Safety analysis outcome measure of non-fatal serious adverse event was defined by International Conference on Harmonisation (ICH) criteria. Fatal events were excluded as deaths were a secondary efficacy outcome (see outcome measure: incidence rate of death (all-cause)). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 100 person-years
        number (confidence interval 95%)
    4.17 (3.88 to 4.48)
    4.18 (3.89 to 4.49)
    Statistical analysis title
    		 Statistical Analysis for Non-fatal SAE
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Incidence rate ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.1

    Secondary: Incidence Rate of Diabetes

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    End point title
    		 Incidence Rate of Diabetes
    End point description
    Safety analysis outcome measure of diabetes was defined as new diagnosis of diabetes with initiation of anti-diabetic agent. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrolment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3864
    3867
    Units: events per 100 person-years
        number (confidence interval 95%)
    1.18 (1.04 to 1.34)
    0.91 (0.79 to 1.06)
    Statistical analysis title
    		 Statistical Analysis for Rate of Diabetes
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7731
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Incidence rate ratio
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.07
         upper limit
    		 1.57

    Secondary: Incidence Rate of Myalgia, Muscle Weakness or Myopathy

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    End point title
    		 Incidence Rate of Myalgia, Muscle Weakness or Myopathy
    End point description
    Safety analysis outcome measure of myalgia, muscle weakness or myopathy which were grade 3 or higher or treatment-limiting. Grade 3 or higher includes grade 3 and 4 events, where grade 3 refers to severe and grade 4 to life-threatening according to DAIDS AE Grading Table (version 2.1). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrolment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 100 person-years
        number (confidence interval 95%)
    0.46 (0.38 to 0.56)
    0.29 (0.23 to 0.38)
    Statistical analysis title
    		 Analysis for Incidence Rate of Myalgia
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Incidence rate ratio
    Point estimate
    1.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.14
         upper limit
    		 2.19

    Secondary: Incidence Rate of Rhabdomyolysis

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    End point title
    		 Incidence Rate of Rhabdomyolysis
    End point description
    Safety analysis outcome measure of rhabdomyolysis which was grade 3 or higher or treatment-limiting. Grade 3 or higher includes grade 3 and 4 events, where grade 3 refers to severe and grade 4 to life-threatening, according to DAIDS AE Grading Table (version 2.1). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo). Due to small number of events, there was no adjustment for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrolment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 100 person-years
        number (confidence interval 95%)
    0.015 (0.005 to 0.046)
    0.020 (0.007 to 0.052)
    Statistical analysis title
    		 Statistical Analysis 1 for Rate of Rhabdomyolysis
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 3.37

    Secondary: Incidence Rate of Grade 3 or Higher ALT

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    End point title
    		 Incidence Rate of Grade 3 or Higher ALT
    End point description
    Safety analysis outcome measure of Grade 3 or higher alanine transaminase (ALT). Grade 3 or higher includes grade 3 and 4 events, where grade 3 refers to severe and grade 4 to life-threatening, according to DAIDS AE Grading Table (version 2.1). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo). Due to small number of events, there was no adjustment for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrolment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 100 person-years
        number (confidence interval 95%)
    0.059 (0.033 to 0.10)
    0.044 (0.023 to 0.085)
    Statistical analysis title
    		 Statistical Analysis 1 for Grade 3 or Higher ALT
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Incidence rate ratio
    Point estimate
    1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 3.18

    Secondary: Incidence Rate of Adverse Event (AE)

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    End point title
    		 Incidence Rate of Adverse Event (AE)
    End point description
    Safety analysis outcome measure of any AE. AE collection included events of grade ≥3, those that were serious (defined by International Conference on Harmonisation (ICH) criteria) or treatment-limiting, and targeted diagnosis of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Fatal events were excluded as deaths were a secondary efficacy outcome (see outcome measure: incidence rate of death (all-cause)). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888
    3881
    Units: events per 100 person-years
        number (confidence interval 95%)
    8.83 (8.32 to 9.31)
    8.49 (8.05 to 8.95)
    Statistical analysis title
    		 Statistical Analysis 1 for Incidence Rate of AE
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Incidence rate ratio
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 1.12

    Secondary: Fasting Low-density Lipoprotein Cholesterol (LDL-C)

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    End point title
    		 Fasting Low-density Lipoprotein Cholesterol (LDL-C)
    End point description
    LDL-C level was derived as LDL-C calculated according to the Friedewald formula at triglycerides ≤400 mg/dL, and direct LDL-C at triglycerides >400 to <500 mg/dL. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    At entry and months 12, 24, 36, 48, 60, 72, 84. Participants’ follow-up time on study varied, depending on their time of enrolment.
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3682 [2]
    3667 [3]
    Units: mg/dL
    median (inter-quartile range (Q1-Q3))
        Entry: LDL-C
    107 (87 to 129)
    106 (86 to 127)
        Month 12: LDL-C
    74 (58 to 92)
    105 (85 to 126)
        Month 24: LDL-C
    75 (59 to 93)
    104 (84 to 126)
        Month 36: LDL-C
    73 (57 to 92)
    104 (83 to 126)
        Month 48: LDL-C
    73 (56 to 92)
    103 (83 to 124)
        Month 60: LDL-C
    73 (56 to 93)
    103 (82 to 125)
        Month 72: LDL-C
    74 (57 to 95)
    101 (82 to 122)
        Month 84: LDL-C
    75 (59 to 98)
    98 (81 to 121)
    Notes
    [2] - Month(no. analysed): 12(3341) 24(3088) 36(2810) 48(2525) 60(2057) 72(1170) 84(492)
    [3] - Month(no. analysed): 12(3321) 24(3122) 36(2792) 48(2526) 60(2053) 72(1114) 84(452)
    No statistical analyses for this end point

    Secondary: Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C)

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    End point title
    		 Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C)
    End point description
    Non-HDL cholesterol levels were calculated as total cholesterol minus HDL cholesterol. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    At entry and months 12, 24, 36, 48, 60, 72, 84. Participants’ follow-up time on study varied, depending on their time of enrolment.
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3714 [4]
    3681 [5]
    Units: mg/dL
    median (inter-quartile range (Q1-Q3))
        Entry: non-HDL-C
    133 (110 to 158)
    132 (108 to 157)
        Month 12: non-HDL-C
    97 (80 to 118)
    131 (108 to 156)
        Month 24: non-HDL-C
    98 (80 to 121)
    131 (108 to 156)
        Month 36: non-HDL-C
    97 (78 to 118)
    130 (107 to 154)
        Month 48: non-HDL-C
    96 (77 to 119)
    128 (106 to 154)
        Month 60: non-HDL-C
    96 (78 to 120)
    127 (104 to 153)
        Month 72: non-HDL-C
    95 (78 to 121)
    124 (104 to 150)
        Month 84: non-HDL-C
    99 (80 to 124)
    123 (101 to 151)
    Notes
    [4] - Mth: No Analysed 12:3367 24:3116 36:2835 48:2542 60:2073 72:1180 84:496
    [5] - Mth: No Analysed 12:3354 24:3143 36:2816 48:2544 60:2074 72:1121 84:455
    No statistical analyses for this end point

    Secondary: Incidence Rate of Serious COVID-19

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    End point title
    		 Incidence Rate of Serious COVID-19
    End point description
    Serious COVID-19 was defined as COVID-19 that resulted in hospitalization or death or was life-threatening as per the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline E2A definition. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for GBD region to account for regional differences. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From January 1, 2020 through end of study; the median follow-up time was 3.3 years.
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3451
    3454
    Units: events per 100 person-years
        number (confidence interval 95%)
    0.45 (0.34 to 0.59)
    0.60 (0.48 to 0.77)
    Statistical analysis title
    		 Statistical Analysis for Rate of Serious COVID-1D
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    6905
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.08

    Secondary: Incidence Rate of COVID-19

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    End point title
    		 Incidence Rate of COVID-19
    End point description
    COVID-19 was defined as COVID-19 clinical diagnosis or positive test result (SARS-CoV-2 PCR or rapid antigen tests). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios (prescribed pitavastatin compared to placebo) from Poisson regression models, adjusted for GBD region to account for regional differences. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
    End point type
    Secondary
    End point timeframe
    From January 1, 2020 through end of study; the median follow-up time was 3.3 years.
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3451
    3454
    Units: events per 100 person-years
        number (confidence interval 95%)
    8.79 (8.22 to 9.39)
    8.35 (7.80 to 8.93)
    Statistical analysis title
    		 Statistical Anal. 1 for Incidence Rate of COVID-19
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    6905
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Incidence rate ratio
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.16

    Other pre-specified: Incidence Rate of MACE by Sex

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    End point title
    		 Incidence Rate of MACE by Sex
    End point description
    Subgroup analysis of the primary composite MACE outcome measure (as described above) by sex. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The Cox proportional hazards models described for the primary outcome above were expanded to include sex and interaction of sex and treatment, to evaluate modification of statin effect.
    End point type
    Other pre-specified
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrolment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888 [6]
    3881 [7]
    Units: events per 1000 person-years
    number (confidence interval 95%)
        Among females
    3.9 (2.7 to 5.8)
    6.2 (4.6 to 8.4)
        Among males
    5.5 (4.4 to 6.9)
    8.5 (7.1 to 10.2)
    Notes
    [6] - 1211 females 2677 males
    [7] - 1208 females 2673 males
    Statistical analysis title
    		 Analysis 1 for Incidence Rate of MACE by Sex
    Statistical analysis description
    Evaluation of treatment effect modification by sex (i.e. pitavastatin effect differing in females compared to males).
    Comparison groups
    Placebo v Pitavastatin
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.98 [8]
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [8] - Treatment effect modification by sex was evaluated via interaction of treatment and sex in the Cox proportional hazards regression model.
    Statistical analysis title
    		 Analysis 2 for Incidence Rate of MACE by Sex
    Statistical analysis description
    Evaluation of pitavastatin effect among females
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.04
    Statistical analysis title
    		 Analysis 3 for Incidence Rate of MACE by Sex
    Statistical analysis description
    Evaluation of pitavastatin effect among males
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 0.86

    Other pre-specified: Incidence Rate of MACE by Race

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    End point title
    		 Incidence Rate of MACE by Race
    End point description
    Subgroup analysis of the primary composite MACE outcome measure (as described above) by race. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The Cox proportional hazards models described for the primary outcome above were expanded to include race and interaction of race and treatment, to evaluate modification of statin effect.
    End point type
    Other pre-specified
    End point timeframe
    From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
    End point values
    		 Pitavastatin Placebo
    Number of subjects analysed
    3888 [9]
    3881 [10]
    Units: events per 1000 person-years
    number (confidence interval 95%)
        Among Asians
    1.6 (0.7 to 3.7)
    7.0 (4.6 to 10.6)
        Among Blacks
    5.8 (4.3 to 7.7)
    8.7 (6.9 to 10.9)
        Among Whites
    5.6 (4.1 to 7.7)
    7.5 (5.7 to 9.9)
        Among Other
    5.0 (2.7 to 9.4)
    5.7 (3.1 to 10.6)
    Notes
    [9] - Among Asians: 571 Among Blacks: 1569 Among Whites: 1364 Among Other: 384
    [10] - Among Asians: 567 Among Blacks: 1639 Among Whites: 1340 Among Other: 335
    Statistical analysis title
    		 Analysis 1 for Incidence Rate of MACE by Race
    Statistical analysis description
    Evaluation of treatment effect modification by race (i.e. pitavastatin effect differing between races).
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.14 [11]
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [11] - Treatment effect modification by race was evaluated via interaction of treatment and race in the Cox proportional hazards regression model.
    Statistical analysis title
    		 Analysis 2 for Incidence Rate of MACE by Race
    Statistical analysis description
    Pitavastatin effect among Asians from subgroup analysis by race. Hazard ratio is shown as pitavastatin/placebo among Asians. Number analysed in Pitavastatin group 571, Number analysed in Placebo group 567
    Comparison groups
    Pitavastatin v Placebo
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.59
    Statistical analysis title
    		 Analysis 3 for Incidence Rate of MACE by Race
    Statistical analysis description
    Pitavastatin effect among Blacks from subgroup analysis by race. Hazard ratio is shown as pitavastatin/placebo among Blacks. Number analysed in Pitavastatin group 1569, Number analysed in Placebo group 1639
    Comparison groups
    Placebo v Pitavastatin
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.96
    Statistical analysis title
    		 Analysis 4 for Incidence Rate of MACE by Race
    Statistical analysis description
    Pitavastatin effect among Whites from subgroup analysis by race. Hazard ratio is shown as pitavastatin/placebo among Whites. Number analysed in Pitavastatin group 1364, Number analysed in Placebo group 1340
    Comparison groups
    Placebo v Pitavastatin
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1.13
    Statistical analysis title
    		 Analysis 5 for Incidence Rate of MACE by Race
    Statistical analysis description
    Pitavastatin effect among Other race from subgroup analysis by race. Hazard ratio is shown as pitavastatin/placebo among Other race. Number analysed in Pitavastatin group 384, Number analysed in Placebo group 335
    Comparison groups
    Placebo v Pitavastatin
    Number of subjects included in analysis
    7769
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 2.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From entry through end of study. Follow-up time varied depending on time of enrolment (the median follow-up time was 5.6 years)
    Adverse event reporting additional description
    AE collection included events of grade ≥3, those that were serious (per ICH criteria) or treatment-limiting, and all new diagnoses of diabetes. Targeted clinical events for pitavastatin efficacy evaluation including death were not reported as AEs. The highest grade of each event type was recorded rather than the number of occurrences.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Pitavastatin
    Reporting group description
    		 Participants received pitavastatin once a day for the entire time they were in study follow-up.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomly assigned to receive placebo tablet once a day for their entire study duration.

    Serious adverse events
    		 Pitavastatin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    750 / 3888 (19.29%)
    755 / 3881 (19.45%)
         number of deaths (all causes)
    126
    143
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anal canal neoplasms malignant
         subjects affected / exposed
    3 / 3888 (0.08%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphomas NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct neoplasms malignant
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder neoplasms malignant
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone neoplasms unspecified malignancy
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast and nipple neoplasms benign
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast and nipple neoplasms malignant
         subjects affected / exposed
    7 / 3888 (0.18%)
    7 / 3881 (0.18%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burkitt’s lymphomas
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system neoplasms malignant NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix neoplasms malignant
         subjects affected / exposed
    3 / 3888 (0.08%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal neoplasms malignant
         subjects affected / exposed
    3 / 3888 (0.08%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine neoplasms malignant and unspecified NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extranodal marginal zone B-cell lymphomas (low grade B-cell)
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fallopian tube neoplasms malignant
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrous histiocytomas malignant
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder neoplasms malignant
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric neoplasms malignant
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glial tumours malignant
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gliomas benign
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic neoplasms malignant
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hodgkin’s disease NEC
         subjects affected / exposed
    4 / 3888 (0.10%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal neoplasms malignant
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukaemias acute lymphocytic
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukaemias chronic myeloid
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lip and oral cavity neoplasms malignant
         subjects affected / exposed
    2 / 3888 (0.05%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liposarcomas malignant
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphomas unspecified NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinal neoplasms malignant
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to specified sites
         subjects affected / exposed
    0 / 3888 (0.00%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myeloproliferative disorders (excl leukaemias)
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms malignant site unspecified NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system neoplasms unspecified malignancy NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    5 / 3881 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Hodgkin’s lymphomas NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell neoplasms malignant of the respiratory tract cell type specified
         subjects affected / exposed
    3 / 3888 (0.08%)
    6 / 3881 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oncologic complications and emergencies
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal, nasopharyngeal and tonsillar neoplasms malignant and unspecified
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian neoplasms benign
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian neoplasms malignant (excl germ cell)
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myelomas
         subjects affected / exposed
    3 / 3888 (0.08%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic neoplasms malignant
         subjects affected / exposed
    6 / 3888 (0.15%)
    5 / 3881 (0.13%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal neoplasms malignant
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal pelvis and ureter neoplasms malignant
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract and pleural neoplasms malignant cell type unspecified NEC
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract small cell carcinomas
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary gland neoplasms malignant
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin melanomas (excl ocular)
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin neoplasms benign
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin neoplasms malignant and unspecified (excl melanoma)
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue neoplasms benign NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine neoplasms benign
         subjects affected / exposed
    3 / 3888 (0.08%)
    5 / 3881 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval neoplasms malignant
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Accelerated and malignant hypertension
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysms and dissections
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic embolism and thrombosis
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse and shock
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhages NEC
         subjects affected / exposed
    2 / 3888 (0.05%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedemas
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-site specific embolism and thrombosis
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-site specific necrosis and vascular insufficiency NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral embolism and thrombosis
         subjects affected / exposed
    9 / 3888 (0.23%)
    11 / 3881 (0.28%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vasoconstriction, necrosis and vascular insufficiency
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose veins NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular hypertensive disorders NEC
         subjects affected / exposed
    6 / 3888 (0.15%)
    7 / 3881 (0.18%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular hypotensive disorders
         subjects affected / exposed
    3 / 3888 (0.08%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitides NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abdominal therapeutic procedures NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract and gallbladder therapeutic procedures
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac therapeutic procedures NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac valve therapeutic procedures
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial therapeutic procedures
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric therapeutic procedures
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia repairs
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint therapeutic procedures
         subjects affected / exposed
    2 / 3888 (0.05%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal therapeutic procedures
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb therapeutic procedures
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Penile therapeutic procedures
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric therapies
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal therapeutic procedures
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestine therapeutic procedures
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue therapeutic procedures NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spine and spinal cord therapeutic procedures
         subjects affected / exposed
    2 / 3888 (0.05%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Therapeutic procedures NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine therapeutic procedures
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortions spontaneous
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenic conditions
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature altered
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile disorders
         subjects affected / exposed
    5 / 3888 (0.13%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General signs and symptoms NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Healing abnormal NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernias NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammations
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain and discomfort NEC
         subjects affected / exposed
    16 / 3888 (0.41%)
    24 / 3881 (0.62%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcers NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Acute and chronic sarcoidosis
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Allergic conditions NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Allergies to foods, food additives, drugs and other chemicals
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic and anaphylactoid responses
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Criminal activity
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast disorders NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix disorders NEC
         subjects affected / exposed
    3 / 3888 (0.08%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menstruation and uterine bleeding NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menstruation with increased bleeding
         subjects affected / exposed
    4 / 3888 (0.10%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian and fallopian tube cysts and neoplasms
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvis and broad ligament disorders NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate and seminal vesicles infections and inflammations
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic neoplasms and hypertrophy
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive tract disorders NEC (excl neoplasms)
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testicular and epididymal disorders NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine disorders NEC
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulvovaginal disorders NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Breathing abnormalities
         subjects affected / exposed
    12 / 3888 (0.31%)
    9 / 3881 (0.23%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial conditions NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm and obstruction
         subjects affected / exposed
    30 / 3888 (0.77%)
    22 / 3881 (0.57%)
         occurrences causally related to treatment / all
    0 / 30
    0 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conditions associated with abnormal gas exchange
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coughing and associated symptoms
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal and adjacent sites disorders NEC (excl infections and neoplasms)
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract signs and symptoms
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinal disorders
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal disorders NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parenchymal lung disorders NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax and pleural effusions NEC
         subjects affected / exposed
    7 / 3888 (0.18%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertensions
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedemas
         subjects affected / exposed
    3 / 3888 (0.08%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary thrombotic and embolic conditions
         subjects affected / exposed
    11 / 3888 (0.28%)
    21 / 3881 (0.54%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failures (excl neonatal)
         subjects affected / exposed
    6 / 3888 (0.15%)
    6 / 3881 (0.15%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract disorders NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety symptoms
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar disorders
         subjects affected / exposed
    2 / 3888 (0.05%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusion and disorientation
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deliria
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delusional disorders
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delusional symptoms
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressive disorders
         subjects affected / exposed
    6 / 3888 (0.15%)
    10 / 3881 (0.26%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorders NEC
         subjects affected / exposed
    10 / 3888 (0.26%)
    6 / 3881 (0.15%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood alterations with manic symptoms
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood disorders NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attacks and disorders
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder NEC
         subjects affected / exposed
    8 / 3888 (0.21%)
    6 / 3881 (0.15%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizoaffective and schizophreniform disorders
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophrenia NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somatic symptom disorders
         subjects affected / exposed
    3 / 3888 (0.08%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance related and addictive disorders
         subjects affected / exposed
    9 / 3888 (0.23%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal and self-injurious behaviour
         subjects affected / exposed
    33 / 3888 (0.85%)
    28 / 3881 (0.72%)
         occurrences causally related to treatment / all
    1 / 33
    0 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device issues NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct infections and inflammations
         subjects affected / exposed
    0 / 3888 (0.00%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis and cholelithiasis
         subjects affected / exposed
    17 / 3888 (0.44%)
    13 / 3881 (0.33%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis and jaundice
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic and hepatobiliary disorders NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzymes and function abnormalities
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic fibrosis and cirrhosis
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic vascular disorders
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular damage and hepatitis NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive bile duct disorders (excl neoplasms)
         subjects affected / exposed
    1 / 3888 (0.03%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Structural and other bile duct disorders
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Carbohydrate tolerance analyses (incl diabetes)
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac function diagnostic procedures
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ECG investigations
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary function diagnostic procedures
         subjects affected / exposed
    8 / 3888 (0.21%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Physical examination procedures and organ system status
         subjects affected / exposed
    0 / 3888 (0.00%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet analyses
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Red blood cell analyses
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal function analyses
         subjects affected / exposed
    4 / 3888 (0.10%)
    5 / 3881 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skeletal and cardiac muscle analyses
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tissue enzyme analyses NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Triglyceride analyses
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular tests NEC (incl blood pressure)
         subjects affected / exposed
    3 / 3888 (0.08%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell analyses
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal and gastrointestinal injuries NEC
         subjects affected / exposed
    2 / 3888 (0.05%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental exposures to product
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral injuries NEC
         subjects affected / exposed
    10 / 3888 (0.26%)
    8 / 3881 (0.21%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chemical injuries
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest and respiratory tract injuries NEC
         subjects affected / exposed
    4 / 3888 (0.10%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conditions caused by cold
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye injuries NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractures and dislocations NEC
         subjects affected / exposed
    7 / 3888 (0.18%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal and hepatobiliary procedural complications
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb fractures and dislocations
         subjects affected / exposed
    43 / 3888 (1.11%)
    50 / 3881 (1.29%)
         occurrences causally related to treatment / all
    0 / 43
    0 / 50
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle, tendon and ligament injuries
         subjects affected / exposed
    3 / 3888 (0.08%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal procedural complications
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-site specific injuries NEC
         subjects affected / exposed
    14 / 3888 (0.36%)
    12 / 3881 (0.31%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-site specific procedural complications
         subjects affected / exposed
    2 / 3888 (0.05%)
    7 / 3881 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdoses NEC
         subjects affected / exposed
    4 / 3888 (0.10%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fractures and dislocations
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poisoning and toxicity
         subjects affected / exposed
    3 / 3888 (0.08%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product administration errors and issues
         subjects affected / exposed
    0 / 3888 (0.00%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation injuries
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Site specific injuries NEC
         subjects affected / exposed
    3 / 3888 (0.08%)
    5 / 3881 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin injuries NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fractures, facial bone fractures and dislocations
         subjects affected / exposed
    1 / 3888 (0.03%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord injuries NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fractures and dislocations
         subjects affected / exposed
    4 / 3888 (0.10%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burns
         subjects affected / exposed
    3 / 3888 (0.08%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic cage fractures and dislocations
         subjects affected / exposed
    6 / 3888 (0.15%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac conduction disorders
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac signs and symptoms NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disorders NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart failures NEC
         subjects affected / exposed
    5 / 3888 (0.13%)
    6 / 3881 (0.15%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic coronary artery disorders
         subjects affected / exposed
    7 / 3888 (0.18%)
    10 / 3881 (0.26%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failures
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valvular disorders
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Noninfectious pericarditis
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial disorders NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rate and rhythm disorders NEC
         subjects affected / exposed
    3 / 3888 (0.08%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular arrhythmias
         subjects affected / exposed
    8 / 3888 (0.21%)
    6 / 3881 (0.15%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmias and cardiac arrest
         subjects affected / exposed
    1 / 3888 (0.03%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Acute polyneuropathies
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alzheimer’s disease (incl subtypes)
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system aneurysms and dissections
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system haemorrhages and cerebrovascular accidents
         subjects affected / exposed
    5 / 3888 (0.13%)
    9 / 3881 (0.23%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system vascular disorders NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical spinal cord and nerve root disorders
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coordination and balance disturbances
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cortical dysfunction NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cranial nerve disorders NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia (excl Alzheimer’s type)
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Demyelinating disorders NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disturbances in consciousness NEC
         subjects affected / exposed
    15 / 3888 (0.39%)
    11 / 3881 (0.28%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathies NEC
         subjects affected / exposed
    2 / 3888 (0.05%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathies toxic and metabolic
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial cranial nerve disorders
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizures
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headaches NEC
         subjects affected / exposed
    6 / 3888 (0.15%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalic conditions
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Increased intracranial pressure disorders
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal cord and nerve root disorders
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Memory loss (excl dementia)
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine headaches
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mononeuropathies
         subjects affected / exposed
    3 / 3888 (0.08%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Motor neurone diseases
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological signs and symptoms NEC
         subjects affected / exposed
    10 / 3888 (0.26%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuromuscular disorders NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic nerve disorders NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesias and dysaesthesias
         subjects affected / exposed
    3 / 3888 (0.08%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paralysis and paresis (excl cranial nerve)
         subjects affected / exposed
    5 / 3888 (0.13%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson’s disease and parkinsonism
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral neuropathies NEC
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizures and seizure disorders NEC
         subjects affected / exposed
    9 / 3888 (0.23%)
    14 / 3881 (0.36%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Speech and language abnormalities
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord and nerve root disorders NEC
         subjects affected / exposed
    4 / 3888 (0.10%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Structural brain disorders NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient cerebrovascular events
         subjects affected / exposed
    3 / 3888 (0.08%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Behaviour and socialisation disturbances
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia deficiencies
         subjects affected / exposed
    2 / 3888 (0.05%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemias NEC
         subjects affected / exposed
    16 / 3888 (0.41%)
    10 / 3881 (0.26%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia of chronic disorders
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathies
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenias NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphatic system disorders NEC
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenias
         subjects affected / exposed
    2 / 3888 (0.05%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenias
         subjects affected / exposed
    3 / 3888 (0.08%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hearing losses
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inner ear signs and symptoms
         subjects affected / exposed
    1 / 3888 (0.03%)
    7 / 3881 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract conditions
         subjects affected / exposed
    12 / 3888 (0.31%)
    6 / 3881 (0.15%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Choroid and vitreous structural change, deposit and degeneration
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucomas (excl congenital)
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iris and uveal tract infections, irritations and inflammations
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic disc abnormalities NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic nerve bleeding and vascular disorders
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orbital infections, inflammations and irritations
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal structural change, deposit and degeneration
         subjects affected / exposed
    3 / 3888 (0.08%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual impairment and blindness (excl colour blindness)
         subjects affected / exposed
    3 / 3888 (0.08%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernias NEC
         subjects affected / exposed
    3 / 3888 (0.08%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute and chronic pancreatitis
         subjects affected / exposed
    10 / 3888 (0.26%)
    11 / 3881 (0.28%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal and rectal disorders NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal and rectal pains
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign neoplasms gastrointestinal (excl oral cavity)
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis (excl infective)
         subjects affected / exposed
    4 / 3888 (0.10%)
    8 / 3881 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic hernias
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea (excl infective)
         subjects affected / exposed
    9 / 3888 (0.23%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal and small intestinal stenosis and obstruction
         subjects affected / exposed
    4 / 3888 (0.10%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcers and perforation
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric and oesophageal haemorrhages
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis (excl infective)
         subjects affected / exposed
    8 / 3888 (0.21%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal and abdominal pains (excl oral and throat)
         subjects affected / exposed
    5 / 3888 (0.13%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal atonic and hypomotility disorders NEC
         subjects affected / exposed
    3 / 3888 (0.08%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammatory disorders NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal signs and symptoms NEC
         subjects affected / exposed
    4 / 3888 (0.10%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stenosis and obstruction NEC
         subjects affected / exposed
    5 / 3888 (0.13%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal ulcers and perforation, site unspecified
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal vascular occlusion and infarction
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingival disorders, signs and symptoms NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids and gastrointestinal varices (excl oesophageal)
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernias
         subjects affected / exposed
    8 / 3888 (0.21%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhages
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ulcers and perforation NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal stenosis and obstruction
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea and vomiting symptoms
         subjects affected / exposed
    8 / 3888 (0.21%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-site specific gastrointestinal haemorrhages
         subjects affected / exposed
    2 / 3888 (0.05%)
    11 / 3881 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis and obstruction
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcers and perforation
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis (excl infective)
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral soft tissue disorders NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal and retroperitoneal disorders
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal inflammations NEC
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary gland disorders NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernias
         subjects affected / exposed
    3 / 3888 (0.08%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedemas
         subjects affected / exposed
    3 / 3888 (0.08%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis and eczema
         subjects affected / exposed
    2 / 3888 (0.05%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis ascribed to specific agent
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipodystrophies
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoriatic conditions
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rashes, eruptions and exanthems NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue ulcerations
         subjects affected / exposed
    1 / 3888 (0.03%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder disorders NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital and urinary tract disorders NEC
         subjects affected / exposed
    2 / 3888 (0.05%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis and nephrotic syndrome
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathies and tubular disorders NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure and impairment
         subjects affected / exposed
    25 / 3888 (0.64%)
    24 / 3881 (0.62%)
         occurrences causally related to treatment / all
    0 / 25
    0 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal lithiasis
         subjects affected / exposed
    4 / 3888 (0.10%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal obstructive disorders
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal vascular and ischaemic conditions
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Structural and obstructive urethral disorders (excl congenital)
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral disorders NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary abnormalities
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract lithiasis NEC
         subjects affected / exposed
    3 / 3888 (0.08%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract signs and symptoms NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal cortical hypofunctions
         subjects affected / exposed
    4 / 3888 (0.10%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperparathyroid disorders
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior pituitary disorders
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthropathies NEC
         subjects affected / exposed
    3 / 3888 (0.08%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone disorders NEC
         subjects affected / exposed
    8 / 3888 (0.21%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cartilage disorders
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture complications
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractures NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc disorders NEC
         subjects affected / exposed
    3 / 3888 (0.08%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint related disorders NEC
         subjects affected / exposed
    4 / 3888 (0.10%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint related signs and symptoms
         subjects affected / exposed
    4 / 3888 (0.10%)
    6 / 3881 (0.15%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic bone disorders
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle infections and inflammations
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle pains
         subjects affected / exposed
    2 / 3888 (0.05%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle related signs and symptoms NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle weakness conditions
         subjects affected / exposed
    2 / 3888 (0.05%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue pain and discomfort
         subjects affected / exposed
    11 / 3888 (0.28%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathies
         subjects affected / exposed
    4 / 3888 (0.10%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthropathies
         subjects affected / exposed
    11 / 3888 (0.28%)
    9 / 3881 (0.23%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthropathies
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spine and neck deformities
         subjects affected / exposed
    7 / 3888 (0.18%)
    5 / 3881 (0.13%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial disorders
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon disorders
         subjects affected / exposed
    0 / 3888 (0.00%)
    5 / 3881 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal and gastrointestinal infections
         subjects affected / exposed
    36 / 3888 (0.93%)
    41 / 3881 (1.06%)
         occurrences causally related to treatment / all
    0 / 36
    0 / 41
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Actinomycotic infectious disorders
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenoviral infections
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical mycobacterial infections
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infections NEC
         subjects affected / exposed
    41 / 3888 (1.05%)
    30 / 3881 (0.77%)
         occurrences causally related to treatment / all
    0 / 41
    0 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone and joint infections
         subjects affected / exposed
    9 / 3888 (0.23%)
    9 / 3881 (0.23%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast infections
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Caliciviral infections
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter infections
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida infections
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system and spinal infections
         subjects affected / exposed
    5 / 3888 (0.13%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridia infections
         subjects affected / exposed
    5 / 3888 (0.13%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cryptococcal infections
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegaloviral infections
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dental and oral soft tissue infections
         subjects affected / exposed
    3 / 3888 (0.08%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infections
         subjects affected / exposed
    0 / 3888 (0.00%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal infections
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infections
         subjects affected / exposed
    4 / 3888 (0.10%)
    6 / 3881 (0.15%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye and eyelid infections
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Female reproductive tract infections
         subjects affected / exposed
    2 / 3888 (0.05%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flaviviral infections
         subjects affected / exposed
    6 / 3888 (0.15%)
    9 / 3881 (0.23%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infections NEC
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus infections
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis virus infections
         subjects affected / exposed
    3 / 3888 (0.08%)
    6 / 3881 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary and spleen infections
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes viral infections
         subjects affected / exposed
    7 / 3888 (0.18%)
    7 / 3881 (0.18%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections NEC
         subjects affected / exposed
    11 / 3888 (0.28%)
    16 / 3881 (0.41%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza viral infections
         subjects affected / exposed
    11 / 3888 (0.28%)
    10 / 3881 (0.26%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Legionella infections
         subjects affected / exposed
    0 / 3888 (0.00%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leptospira infections
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Listeria infections
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract and lung infections
         subjects affected / exposed
    71 / 3888 (1.83%)
    66 / 3881 (1.70%)
         occurrences causally related to treatment / all
    0 / 71
    0 / 66
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Male reproductive tract infections
         subjects affected / exposed
    4 / 3888 (0.10%)
    7 / 3881 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle and soft tissue infections
         subjects affected / exposed
    2 / 3888 (0.05%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neisseria infections
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nematode infections
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthopox viral infections
         subjects affected / exposed
    1 / 3888 (0.03%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae viral infections
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasmodia infections
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis infections
         subjects affected / exposed
    2 / 3888 (0.05%)
    2 / 3881 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinoviral infections
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rickettsial infectious disorders NEC
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonella infections
         subjects affected / exposed
    2 / 3888 (0.05%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis, bacteraemia, viraemia and fungaemia NEC
         subjects affected / exposed
    20 / 3888 (0.51%)
    18 / 3881 (0.46%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shigella infections
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin structures and soft tissue infections
         subjects affected / exposed
    1 / 3888 (0.03%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infections
         subjects affected / exposed
    4 / 3888 (0.10%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal infections
         subjects affected / exposed
    6 / 3888 (0.15%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxoplasma infections
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Treponema infections
         subjects affected / exposed
    6 / 3888 (0.15%)
    10 / 3881 (0.26%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculous infections
         subjects affected / exposed
    11 / 3888 (0.28%)
    13 / 3881 (0.33%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infections
         subjects affected / exposed
    4 / 3888 (0.10%)
    5 / 3881 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infections
         subjects affected / exposed
    23 / 3888 (0.59%)
    15 / 3881 (0.39%)
         occurrences causally related to treatment / all
    0 / 23
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular infections
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infections NEC
         subjects affected / exposed
    5 / 3888 (0.13%)
    8 / 3881 (0.21%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Calcium metabolism disorders
         subjects affected / exposed
    1 / 3888 (0.03%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus (incl subtypes)
         subjects affected / exposed
    3 / 3888 (0.08%)
    11 / 3881 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic complications NEC
         subjects affected / exposed
    2 / 3888 (0.05%)
    4 / 3881 (0.10%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic complications neurological
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorders of purine metabolism
         subjects affected / exposed
    3 / 3888 (0.08%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Elevated triglycerides
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General nutritional disorders NEC
         subjects affected / exposed
    7 / 3888 (0.18%)
    6 / 3881 (0.15%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemic conditions NEC
         subjects affected / exposed
    4 / 3888 (0.10%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic conditions NEC
         subjects affected / exposed
    2 / 3888 (0.05%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipid metabolism and deposit disorders NEC
         subjects affected / exposed
    0 / 3888 (0.00%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidoses (excl diabetic acidoses)
         subjects affected / exposed
    2 / 3888 (0.05%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic alkaloses
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phosphorus metabolism disorders
         subjects affected / exposed
    1 / 3888 (0.03%)
    0 / 3881 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Potassium imbalance
         subjects affected / exposed
    0 / 3888 (0.00%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sodium imbalance
         subjects affected / exposed
    3 / 3888 (0.08%)
    3 / 3881 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Total fluid volume decreased
         subjects affected / exposed
    3 / 3888 (0.08%)
    1 / 3881 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Pitavastatin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    488 / 3888 (12.55%)
    420 / 3881 (10.82%)
    Investigations
    Physical examination procedures and organ system status
         subjects affected / exposed
    62 / 3888 (1.59%)
    65 / 3881 (1.67%)
         occurrences all number
    62
    65
    Renal function analyses
         subjects affected / exposed
    125 / 3888 (3.22%)
    122 / 3881 (3.14%)
         occurrences all number
    125
    122
    Vascular disorders
    Vascular hypertensive disorders NEC
         subjects affected / exposed
    37 / 3888 (0.95%)
    50 / 3881 (1.29%)
         occurrences all number
    37
    50
    Musculoskeletal and connective tissue disorders
    Muscle pains
         subjects affected / exposed
    77 / 3888 (1.98%)
    44 / 3881 (1.13%)
         occurrences all number
    77
    44
    Musculoskeletal and connective tissue pain and discomfort
         subjects affected / exposed
    40 / 3888 (1.03%)
    43 / 3881 (1.11%)
         occurrences all number
    40
    43
    Metabolism and nutrition disorders
    Diabetes mellitus (incl subtypes)
         subjects affected / exposed
    238 / 3888 (6.12%)
    184 / 3881 (4.74%)
         occurrences all number
    238
    184
    General nutritional disorders NEC
         subjects affected / exposed
    66 / 3888 (1.70%)
    44 / 3881 (1.13%)
         occurrences all number
    66
    44

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2015
    Upper threshold for ASCVD risk score eligibility was increased from <7.5% to ≤10%; those between 7.5% and ≤10% had to have LDL <160 mg/dL
    17 Aug 2016
    Upper threshold for ASCVD risk score eligibility was increased from 10% to 15% along with corresponding changes in LDL thresholds.
    01 Feb 2018
    Future enrolment was restricted to exclude candidates with ASCVD risk score <2.5%
    28 Mar 2018
    Study sample size was increased by approximately 1000 participants (to 7500 participants); follow-up duration was increased by one year (to up to 7 years)
    16 May 2018
    Addition of the EU protocol
    29 May 2018
    Future enrolment was restricted to exclude candidates with ASCVD risk score <5%
    01 Apr 2019
    Vital status and endpoint follow-up after premature study discontinuation were implemented; follow-up was extended to 8 years; originally planned (tentative, if requested by DSMB) efficacy/futility look at 20% of information was removed
    16 May 2022
    Follow-up was extended until the study reaches its target of 288 primary MACE endpoints, or otherwise recommended for closure by the DSMB; COVID-19-related secondary objectives introduced with the REPRIEVE NOSI supplement were added

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The highest grade of each event type experienced by participants was reported, hence the number of occurrences recorded is the same as the number of subjects affected. Causality was attributed by site teams and may not reflect casual relatedness.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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