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    Clinical Trial Results:
    Open-Label Extension Study of EFC12492, R727-CL-1112, EFC12732 and LTS11717 Studies to Assess the Long-Term Safety and Efficacy of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia

    Summary
    EudraCT number
    2013-002572-40
    Trial protocol
    IT   ES   BE   NL   GB   NO   CZ   FI   AT   DE   DK   PT   RO   HU   BG  
    Global end of trial date
    30 Jun 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Jul 2018
    First version publication date
    15 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LTS13463
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01954394
    WHO universal trial number (UTN)
    U1111-1143-3810
    Other trial identifiers
    ODYSSEY OLE : Other Identifier
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin , France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the long-term safety of alirocumab when added to currently available lipid-modifying drug therapy in subjects with heterozygous familial hypercholesterolemia (heFH) who have completed one of the following studies: EFC12492, R727-CL-1112, EFC12732 & LTS11717.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    All subjects received a stable dose of statin (rosuvastatin, simvastatin or atorvastatin) with or without other lipid-modifying therapy (LMT) as clinically indicated throughout the duration of study.
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Dec 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 133
    Country: Number of subjects enrolled
    Norway: 57
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Spain: 78
    Country: Number of subjects enrolled
    Sweden: 12
    Country: Number of subjects enrolled
    United Kingdom: 52
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 4
    Country: Number of subjects enrolled
    Czech Republic: 76
    Country: Number of subjects enrolled
    Denmark: 27
    Country: Number of subjects enrolled
    Finland: 7
    Country: Number of subjects enrolled
    France: 75
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Argentina: 4
    Country: Number of subjects enrolled
    Canada: 49
    Country: Number of subjects enrolled
    Israel: 23
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Russian Federation: 39
    Country: Number of subjects enrolled
    South Africa: 167
    Country: Number of subjects enrolled
    United States: 150
    Worldwide total number of subjects
    986
    EEA total number of subjects
    553
    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)
    772
    From 65 to 84 years
    212
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 177 centers in 24 countries. Overall, 986 subjects who completed study EFC12492 (NCT01623115), R727-CL-1112 (NCT01709500), EFC12732 (NCT01617655) and LTS11717 (NCT01507831) were enrolled between December 2013 and December 2014.

    Pre-assignment
    Screening details
    The Day 1 visit of this study was: the end of treatment visit of the 78-week treatment period for subjects who completed EFC12492, R727-CL-1112 and EFC12732; and the end of study visit i.e. 8 weeks after completion of the 78-week treatment period for subjects who completed LTS11717.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Alirocumab: All Subjects
    Arm description
    All subjects who received alirocumab/placebo in the parent studies and received alirocumab 75 mg or 150 mg subcutaneous (SC) injection every 2 weeks (Q2W) added to stable LMT for up to 168 additional weeks in this study.
    Arm type
    Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    SAR236553, REGN727
    Other name
    Praluent
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Alirocumab administered as SC injection in the abdomen, thigh, or outer area of upper arm by self-injection or by another designated person.

    Number of subjects in period 1
    Alirocumab: All Subjects
    Started
    986
    Treated
    985
    Completed
    899
    Not completed
    87
         Related to Study Drug administration
             4
          Other than specified above
             31
         Subject Moved
             4
         Poor compliance to protocol
             14
         Enrolled but not treated
             1
         Adverse Event
             33

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alirocumab: All Subjects
    Reporting group description
    All subjects who received alirocumab/placebo in the parent studies and received alirocumab 75 mg or 150 mg subcutaneous (SC) injection every 2 weeks (Q2W) added to stable LMT for up to 168 additional weeks in this study.

    Reporting group values
    Alirocumab: All Subjects Total
    Number of subjects
    986 986
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.4 ± 11.9 -
    Gender categorical
    Units: Subjects
        Female
    436 436
        Male
    550 550
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    39 39
        Not Hispanic or Latino
    940 940
        Unknown or Not Reported
    7 7
    Race/Ethnicity, Customized
    Units: Subjects
        White
    939 939
        Black or African American
    4 4
        Asian
    8 8
        American Indian or Alaska Native
    3 3
        Native Hawaiian or Other Pacific Islander
    1 1
        Other
    11 11
        White/Black or African American
    11 11
        White/Asian
    7 7
        White/American Indian or Alaska Native
    1 1
        Black or African American/Asian
    1 1
    Calculated low- density lipoprotein cholesterol (LDL-C) in mg/dL
    Calculated LDL-C in mg/dL from Friedewald formula (LDL-C = Total cholesterol - High-density lipoprotein cholesterol - [Triglyceride/5]). This parameter was evaluated at the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717).
    Units: mg/dL
        arithmetic mean (standard deviation)
    152.0 ± 53.2 -
    Calculated LDL-C in mmol/L
    This parameter was evaluated at the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717).
    Units: mmol/L
        arithmetic mean (standard deviation)
    3.936 ± 1.379 -
    Subject analysis sets

    Subject analysis set title
    Placebo to Alirocumab 75 or 150 mg Q2W
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Alirocumab 75 mg or 150 mg SC injection Q2W added to stable LMT for up to 168 weeks in subjects who received placebo in the parent studies. Subjects from parent study EFC12732 (NCT01617655) started with alirocumab 150 mg Q2W and subjects from parent studies EFC12492 (NCT01623115), R727-CL-1112 (NCT01709500) and LTS11717 (NCT01507831) started with alirocumab 75 mg Q2W. Alirocumab doses could be either up-titrated from 75 to 150 mg Q2W or down-titrated from 150 to 75 mg Q2W from Week 12 or maintained according to the investigator judgement and low-density lipoprotein cholesterol (LDL-C) values.

    Subject analysis set title
    Alirocumab to Alirocumab 75 or 150 mg Q2W
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Alirocumab 75 mg or 150 mg SC injection Q2W added to stable LMT for up to 168 additional weeks in subjects who received Alirocumab in the parent studies. Subjects from parent study EFC12732 (NCT01617655) started with alirocumab 150 mg Q2W and subjects from parent studies EFC12492 (NCT01623115), R727-CL-1112 (NCT01709500) and LTS11717 (NCT01507831) started with alirocumab 75 mg Q2W. Alirocumab doses could be either up-titrated from 75 to 150 mg Q2W or down-titrated from 150 to 75 mg Q2W from Week 12 or maintained according to the investigator judgement and LDL-C values.

    Subject analysis sets values
    Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects
    330
    655
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.8 ± 11.4
    54.1 ± 12.1
    Gender categorical
    Units: Subjects
        Female
    148
    287
        Male
    182
    368
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    12
    27
        Not Hispanic or Latino
    317
    623
        Unknown or Not Reported
    1
    5
    Race/Ethnicity, Customized
    Units: Subjects
        White
    310
    628
        Black or African American
    2
    2
        Asian
    2
    6
        American Indian or Alaska Native
    1
    2
        Native Hawaiian or Other Pacific Islander
    1
    0
        Other
    4
    7
        White/Black or African American
    6
    5
        White/Asian
    2
    5
        White/American Indian or Alaska Native
    1
    0
        Black or African American/Asian
    1
    0
    Calculated low- density lipoprotein cholesterol (LDL-C) in mg/dL
    Calculated LDL-C in mg/dL from Friedewald formula (LDL-C = Total cholesterol - High-density lipoprotein cholesterol - [Triglyceride/5]). This parameter was evaluated at the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717).
    Units: mg/dL
        arithmetic mean (standard deviation)
    148.8 ± 48.8
    153.5 ± 55.3
    Calculated LDL-C in mmol/L
    This parameter was evaluated at the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717).
    Units: mmol/L
        arithmetic mean (standard deviation)
    3.854 ± 1.265
    3.977 ± 1.432

    End points

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    End points reporting groups
    Reporting group title
    Alirocumab: All Subjects
    Reporting group description
    All subjects who received alirocumab/placebo in the parent studies and received alirocumab 75 mg or 150 mg subcutaneous (SC) injection every 2 weeks (Q2W) added to stable LMT for up to 168 additional weeks in this study.

    Subject analysis set title
    Placebo to Alirocumab 75 or 150 mg Q2W
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Alirocumab 75 mg or 150 mg SC injection Q2W added to stable LMT for up to 168 weeks in subjects who received placebo in the parent studies. Subjects from parent study EFC12732 (NCT01617655) started with alirocumab 150 mg Q2W and subjects from parent studies EFC12492 (NCT01623115), R727-CL-1112 (NCT01709500) and LTS11717 (NCT01507831) started with alirocumab 75 mg Q2W. Alirocumab doses could be either up-titrated from 75 to 150 mg Q2W or down-titrated from 150 to 75 mg Q2W from Week 12 or maintained according to the investigator judgement and low-density lipoprotein cholesterol (LDL-C) values.

    Subject analysis set title
    Alirocumab to Alirocumab 75 or 150 mg Q2W
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Alirocumab 75 mg or 150 mg SC injection Q2W added to stable LMT for up to 168 additional weeks in subjects who received Alirocumab in the parent studies. Subjects from parent study EFC12732 (NCT01617655) started with alirocumab 150 mg Q2W and subjects from parent studies EFC12492 (NCT01623115), R727-CL-1112 (NCT01709500) and LTS11717 (NCT01507831) started with alirocumab 75 mg Q2W. Alirocumab doses could be either up-titrated from 75 to 150 mg Q2W or down-titrated from 150 to 75 mg Q2W from Week 12 or maintained according to the investigator judgement and LDL-C values.

    Primary: Percentage of Subjects Who Experienced Adverse Events (AEs)

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    End point title
    Percentage of Subjects Who Experienced Adverse Events (AEs) [1]
    End point description
    Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the ‘treatment-emergent period’ (the time from the first dose of alirocumab in this study up to the last dose of alirocumab received in this study +70 days). Clinically significant lab and vital sign abnormalities were to be reported as AEs. Analysis performed on all enrolled subjects who received at least one dose or part of a dose of alirocumab in this study.
    End point type
    Primary
    End point timeframe
    Up to 10 weeks after last study drug administration (maximum of 176 weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety analyses were descriptive in nature.
    End point values
    Alirocumab: All Subjects Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects analysed
    985
    330
    655
    Units: percentage of subjects
    number (not applicable)
        Any AE
    86.2
    83.9
    87.3
        Any Serious AE
    21.5
    20.6
    22.0
        Any AE leading to treatment discontinuation
    3.4
    3.0
    3.5
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Calculated LDL-C at Weeks 8, 24, 48, 72, 96, 120, 144 and 168

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    End point title
    Percent Change From Baseline in Calculated LDL-C at Weeks 8, 24, 48, 72, 96, 120, 144 and 168
    End point description
    Baseline here corresponds to the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717). Post-baseline on-treatment data was obtained from Week 8 onwards up to Week 168 in this study. Modified ITT (mITT) population: all enrolled and treated subjects with 1 baseline (from parent study) and at least 1 post-baseline calculated LDL-C value on-treatment. Here, “Number analysed”(n) = subjects evaluable at specified time-points. This number decreased significantly with visit because of the possibility to switch to commercial alirocumab.
    End point type
    Secondary
    End point timeframe
    Parent Baseline, Weeks 8, 24, 48, 72, 96, 120, 144, and 168
    End point values
    Alirocumab: All Subjects Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects analysed
    974
    323
    651
    Units: percent change
    arithmetic mean (standard deviation)
        Week 8 (n= 917, 306, 611)
    -44.2 ± 27.8
    -44.9 ± 25.9
    -43.8 ± 28.7
        Week 24 (n= 926, 305, 621)
    -46.9 ± 28.7
    -46.9 ± 27.5
    -46.9 ± 29.3
        Week 48 (n= 918, 309, 609)
    -46.9 ± 28.6
    -45.6 ± 28.0
    -47.5 ± 28.8
        Week 72 (n= 887, 293, 594)
    -47.4 ± 26.8
    -47.7 ± 23.5
    -47.3 ± 28.4
        Week 96 (n= 711, 236, 475)
    -47.9 ± 26.8
    -47.4 ± 23.8
    -48.2 ± 28.2
        Week 120 (n= 540, 188, 352)
    -46.8 ± 28.8
    -47.4 ± 24.0
    -46.6 ± 31.1
        Week 144 (n= 198, 69, 129)
    -48.5 ± 25.0
    -46.5 ± 25.8
    -49.6 ± 24.6
        Week 168 (n= 10, 4, 6)
    -48.8 ± 17.8
    -43.6 ± 13.4
    -52.2 ± 20.7
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Weeks 8, 24, 48, 72, 96, 120, 144 and 168

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    End point title
    Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Weeks 8, 24, 48, 72, 96, 120, 144 and 168
    End point description
    Baseline here corresponds to the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717). Post-baseline on-treatment data was obtained from Week 8 onwards up to Week 168 in this study. mITT population. Here, “n” signifies subjects evaluable at specified time-points. This number decreased significantly with visit because of the possibility to switch to commercial alirocumab.
    End point type
    Secondary
    End point timeframe
    Parent Baseline, Weeks 8, 24, 48, 72, 96, 120, 144, and 168
    End point values
    Alirocumab: All Subjects Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects analysed
    974
    323
    651
    Units: mg/dL
    arithmetic mean (standard deviation)
        Week 8 (n= 917, 306, 611)
    -67.0 ± 48.0
    -66.8 ± 45.6
    -67.1 ± 49.2
        Week 24 (n= 926, 305, 621)
    -71.9 ± 51.4
    -70.3 ± 49.5
    -72.7 ± 52.4
        Week 48 (n= 918, 309, 609)
    -71.9 ± 52.8
    -67.8 ± 49.7
    -73.9 ± 54.3
        Week 72 (n= 887, 293, 594)
    -73.7 ± 51.4
    -71.2 ± 44.5
    -74.9 ± 54.5
        Week 96 (n= 711, 236, 475)
    -74.0 ± 52.2
    -70.2 ± 45.9
    -75.9 ± 55.0
        Week 120 (n= 540, 188, 352)
    -74.2 ± 55.2
    -72.3 ± 45.6
    -75.2 ± 59.7
        Week 144 (n= 198, 69, 129)
    -81.6 ± 55.4
    -73.1 ± 50.0
    -86.2 ± 57.8
        Week 168 (n= 10, 4, 6)
    -86.1 ± 42.4
    -66.1 ± 24.7
    -99.4 ± 48.3
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Weeks 8, 24, 48, 72, 96, 120, 144 and 168

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    End point title
    Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Weeks 8, 24, 48, 72, 96, 120, 144 and 168
    End point description
    Baseline here corresponds to the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717). Post-baseline on-treatment data was obtained from Week 8 onwards up to Week 168 in this study. mITT population. Here, “n” signifies subjects evaluable at specified time-points. This number decreased significantly with visit because of the possibility to switch to commercial alirocumab.
    End point type
    Secondary
    End point timeframe
    Parent Baseline, Weeks 8, 24, 48, 72, 96, 120, 144, and 168
    End point values
    Alirocumab: All Subjects Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects analysed
    974
    323
    651
    Units: mmol/L
    arithmetic mean (standard deviation)
        Week 8 (n= 917, 306, 611)
    -1.735 ± 1.242
    -1.729 ± 1.180
    -1.738 ± 1.273
        Week 24 (n= 926, 305, 621)
    -1.863 ± 1.332
    -1.821 ± 1.282
    -1.883 ± 1.356
        Week 48 (n= 918, 309, 609)
    -1.861 ± 1.368
    -1.757 ± 1.286
    -1.914 ± 1.405
        Week 72 (n= 887, 293, 594)
    -1.908 ± 1.332
    -1.843 ± 1.154
    -1.940 ± 1.411
        Week 96 (n= 711, 236, 475)
    -1.916 ± 1.353
    -1.818 ± 1.190
    -1.965 ± 1.426
        Week 120 (n= 540, 188, 352)
    -1.923 ± 1.428
    -1.874 ± 1.180
    -1.949 ± 1.546
        Week 144 (n= 198, 69, 129)
    -2.114 ± 1.436
    -1.894 ± 1.294
    -2.232 ± 1.498
        Week 168 (n= 10, 4, 6)
    -2.229 ± 1.098
    -1.712 ± 0.641
    -2.574 ± 1.252
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) Over Time

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    End point title
    Percentage of Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) Over Time
    End point description
    Baseline here corresponds to the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717). Post-baseline on-treatment data was obtained from Week 8 onwards up to Week 168 in this study. mITT population. Here, "n" signifies subjects evaluable at specified time-points. This number decreased significantly with visit because of the possibility to switch to commercial alirocumab.
    End point type
    Secondary
    End point timeframe
    Parent Baseline, Weeks 8, 24, 48, 72, 96, 120, 144, and 168
    End point values
    Alirocumab: All Subjects Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects analysed
    974
    323
    651
    Units: percentage of subjects
    number (not applicable)
        Baseline (n= 974, 323, 651)
    11.7
    12.1
    11.5
        Week 8 (n= 969, 321, 648)
    81.1
    71.0
    86.1
        Week 24 (n= 926, 305, 621)
    76.1
    77.0
    75.7
        Week 48 (n= 918, 309, 609)
    76.8
    77.7
    76.4
        Week 72 (n= 887, 293, 594)
    79.4
    82.9
    77.6
        Week 96 (n= 711, 236, 475)
    77.6
    79.2
    76.8
        Week 120 (n= 540, 188, 352)
    77.2
    78.2
    76.7
        Week 144 (n= 198, 69, 129)
    73.7
    72.5
    74.4
        Week 168 (n= 10, 4, 6)
    80.0
    75.0
    83.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) Over Time

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    End point title
    Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) Over Time
    End point description
    Baseline here corresponds to the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717). Post-baseline on-treatment data was obtained from Week 8 onwards up to Week 168 in this study. mITT population. Here, “n” signifies subjects evaluable at specified time-points. This number decreased significantly with visit because of the possibility to switch to commercial alirocumab.
    End point type
    Secondary
    End point timeframe
    Parent Baseline, Weeks 8, 24, 48, 72, 96, 120, 144, and 168
    End point values
    Alirocumab: All Subjects Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects analysed
    974
    323
    651
    Units: percentage of subjects
    number (not applicable)
        Baseline (n= 974, 323, 651)
    1.1
    0.9
    1.2
        Week 8 (n= 969, 321, 648)
    60.1
    47.4
    66.4
        Week 24 (n= 926, 305, 621)
    53.2
    53.4
    53.1
        Week 48 (n= 918, 309, 609)
    52.7
    51.1
    53.5
        Week 72 (n= 887, 293, 594)
    54.5
    57.0
    53.2
        Week 96 (n= 711, 236, 475)
    55.3
    53.0
    56.4
        Week 120 (n= 540, 188, 352)
    51.5
    52.7
    50.9
        Week 144 (n= 198, 69, 129)
    47.5
    46.4
    48.1
        Week 168 (n= 10, 4, 6)
    40.0
    50.0
    33.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Calculated LDL-C <70 mg/dL (1.81mmol/L) and/or ≥50% Reduction in Calculated LDL-C From Baseline (if Calculated LDL-C≥70 mg/dL [1.81mmol/L]) Over Time

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    End point title
    Percentage of Subjects With Calculated LDL-C <70 mg/dL (1.81mmol/L) and/or ≥50% Reduction in Calculated LDL-C From Baseline (if Calculated LDL-C≥70 mg/dL [1.81mmol/L]) Over Time
    End point description
    Baseline here corresponds to the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717). Post-baseline on-treatment data was obtained from Week 8 onwards up to Week 168 in this study. mITT population. Here, “n” signifies subjects evaluable at specified time-points. This number decreased significantly with visit because of the possibility to switch to commercial alirocumab.
    End point type
    Secondary
    End point timeframe
    Parent Baseline, Weeks 8, 24, 48, 72, 96, 120, 144, and 168
    End point values
    Alirocumab: All Subjects Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects analysed
    974
    323
    651
    Units: percentage of subjects
    number (not applicable)
        Baseline (n= 974, 323, 651)
    1.1
    0.9
    1.2
        Week 8 (n= 969, 321, 648)
    61.3
    49.5
    67.1
        Week 24 (n= 926, 305, 621)
    54.2
    54.1
    54.3
        Week 48 (n= 918, 309, 609)
    53.7
    52.1
    54.5
        Week 72 (n= 887, 293, 594)
    55.4
    57.3
    54.4
        Week 96 (n= 711, 236, 475)
    56.1
    53.0
    57.7
        Week 120 (n= 540, 188, 352)
    53.1
    53.2
    53.1
        Week 144 (n= 198, 69, 129)
    48.0
    46.4
    48.8
        Week 168 (n= 10, 4, 6)
    40.0
    50.0
    33.3
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Weeks 8, 24, 48, 72, 96, 120, 144 and 168

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    End point title
    Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Weeks 8, 24, 48, 72, 96, 120, 144 and 168
    End point description
    Baseline here corresponds to the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717). Post-baseline on-treatment data was obtained from Week 8 onwards up to Week 168 in this study. mITT population. Here, “n” signifies subjects evaluable at specified time-points. This number decreased significantly with visit because of the possibility to switch to commercial alirocumab.
    End point type
    Secondary
    End point timeframe
    Parent Baseline, Weeks 8, 24, 48, 72, 96, 120, 144, and 168
    End point values
    Alirocumab: All Subjects Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects analysed
    974
    323
    651
    Units: percent change
    arithmetic mean (standard deviation)
        Week 8 (n= 928, 310, 618)
    -37.8 ± 26.0
    -38.1 ± 24.8
    -37.6 ± 26.6
        Week 24 (n= 935, 310, 625)
    -40.5 ± 27.1
    -40.6 ± 25.5
    -40.4 ± 27.9
        Week 48 (n= 926, 310, 616)
    -40.3 ± 26.9
    -39.7 ± 25.5
    -40.6 ± 27.6
        Week 72 (n= 891, 294, 597)
    -40.5 ± 25.3
    -40.8 ± 22.6
    -40.3 ± 26.5
        Week 96 (n= 721, 240, 481)
    -40.3 ± 25.6
    -39.9 ± 23.5
    -40.5 ± 26.6
        Week 120 (n= 546, 188, 358)
    -39.5 ± 27.3
    -41.4 ± 22.1
    -38.4 ± 29.7
        Week 144 (n= 202, 70, 132)
    -41.1 ± 23.6
    -39.8 ± 22.9
    -41.8 ± 24.0
        Week 168 (n= 10, 4, 6)
    -44.9 ± 16.1
    -40.7 ± 12.3
    -47.7 ± 18.8
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Total-cholesterol at Weeks 8, 24, 48, 72, 96, 120, 144 and 168

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    End point title
    Percent Change From Baseline in Total-cholesterol at Weeks 8, 24, 48, 72, 96, 120, 144 and 168
    End point description
    Baseline here corresponds to the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717). Post-baseline on-treatment data was obtained from Week 8 onwards up to Week 168 in this study. mITT population. Here, “n” signifies subjects evaluable at specified time-points. This number decreased significantly with visit because of the possibility to switch to commercial alirocumab.
    End point type
    Secondary
    End point timeframe
    Parent Baseline, Weeks 8, 24, 48, 72, 96, 120, 144, and 168
    End point values
    Alirocumab: All Subjects Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects analysed
    974
    323
    651
    Units: percent change
    arithmetic mean (standard deviation)
        Week 8 (n= 928, 310, 618)
    -27.7 ± 20.2
    -27.9 ± 19.3
    -27.7 ± 20.7
        Week 24 (n= 935, 310, 625)
    -30.1 ± 21.2
    -30.1 ± 20.3
    -30.2 ± 21.6
        Week 48 (n= 926, 310, 616)
    -29.7 ± 21.2
    -29.0 ± 20.5
    -30.0 ± 21.6
        Week 72 (n= 891, 294, 597)
    -30.0 ± 19.9
    -29.9 ± 18.0
    -30.1 ± 20.8
        Week 96 (n= 721, 240, 481)
    -29.6 ± 20.2
    -28.9 ± 18.3
    -29.9 ± 21.1
        Week 120 (n= 546, 188, 358)
    -29.0 ± 21.0
    -30.2 ± 17.2
    -28.4 ± 22.8
        Week 144 (n= 202, 70, 132)
    -30.5 ± 18.8
    -29.1 ± 18.2
    -31.3 ± 19.1
        Week 168 (n= 10, 4, 6)
    -36.4 ± 13.3
    -32.3 ± 12.4
    -39.1 ± 14.3
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Weeks 8, 24, 48, 72, 96, 120, 144 and 168

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    End point title
    Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Weeks 8, 24, 48, 72, 96, 120, 144 and 168
    End point description
    Baseline here corresponds to the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717). Post-baseline on-treatment data was obtained from Week 8 onwards up to Week 168 in this study. mITT population. Here, “n” signifies subjects evaluable at specified time-points. This number decreased significantly with visit because of the possibility to switch to commercial alirocumab.
    End point type
    Secondary
    End point timeframe
    Parent Baseline, Weeks 8, 24, 48, 72, 96, 120, 144, and 168
    End point values
    Alirocumab: All Subjects Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects analysed
    974
    323
    651
    Units: percent change
    arithmetic mean (standard deviation)
        Week 8 (n= 928, 310, 618)
    6.3 ± 17.3
    5.6 ± 17.1
    6.6 ± 17.3
        Week 24 (n= 935, 310, 625)
    5.8 ± 17.1
    5.7 ± 17.4
    5.8 ± 16.9
        Week 48 (n= 926, 310, 616)
    7.2 ± 18.7
    7.1 ± 17.8
    7.2 ± 19.2
        Week 72 (n= 891, 294, 597)
    7.0 ± 19.1
    6.7 ± 17.6
    7.2 ± 19.9
        Week 96 (n= 721, 240, 481)
    7.2 ± 18.7
    7.2 ± 18.8
    7.2 ± 18.7
        Week 120 (n= 546, 188, 358)
    8.1 ± 18.6
    8.0 ± 18.4
    8.1 ± 18.7
        Week 144 (n= 202, 70, 132)
    8.8 ± 23.0
    8.8 ± 19.2
    8.8 ± 24.8
        Week 168 (n= 10, 4, 6)
    -2.8 ± 17.1
    -6.6 ± 26.2
    -0.3 ± 9.9
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Fasting Triglycerides (TGs) at Weeks 8, 24, 48, 72, 96, 120, 144 and 168

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    End point title
    Percent Change From Baseline in Fasting Triglycerides (TGs) at Weeks 8, 24, 48, 72, 96, 120, 144 and 168
    End point description
    Baseline here corresponds to the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717). Post-baseline on-treatment data was obtained from Week 8 onwards up to Week 168 in this study. mITT population. Here, “n” signifies subjects evaluable at specified time-points. This number decreased significantly with visit because of the possibility to switch to commercial alirocumab.
    End point type
    Secondary
    End point timeframe
    Parent Baseline, Weeks 8, 24, 48, 72, 96, 120, 144, and 168
    End point values
    Alirocumab: All Subjects Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects analysed
    974
    323
    651
    Units: percent change
    arithmetic mean (standard deviation)
        Week 8 (n= 927, 309, 618)
    3.5 ± 44.9
    3.4 ± 40.5
    3.5 ± 47.0
        Week 24 (n= 932, 308, 624)
    0.9 ± 44.0
    0.6 ± 39.9
    1.0 ± 45.9
        Week 48 (n= 925, 309, 616)
    3.7 ± 67.2
    0.8 ± 37.5
    5.1 ± 78.0
        Week 72 (n= 889, 293, 596)
    3.8 ± 43.0
    4.3 ± 43.3
    3.6 ± 42.9
        Week 96 (n= 718, 239, 479)
    9.2 ± 54.5
    9.1 ± 53.2
    9.3 ± 55.2
        Week 120 (n= 545, 187, 358)
    6.7 ± 44.8
    -1.2 ± 35.3
    10.8 ± 48.5
        Week 144 (n= 201, 70, 131)
    6.8 ± 45.9
    5.0 ± 38.0
    7.7 ± 49.8
        Week 168 (n= 10, 4, 6)
    -15.0 ± 24.6
    -22.1 ± 21.9
    -10.3 ± 27.1
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Lipoprotein (a) at Weeks 48, 96, 144 and 168

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    End point title
    Percent Change From Baseline in Lipoprotein (a) at Weeks 48, 96, 144 and 168
    End point description
    Baseline here corresponds to the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717). Post-baseline on-treatment data was obtained from Week 8 onwards up to Week 168 in this study. mITT population. Here, “n” signifies subjects evaluable at specified time-points. This number decreased significantly with visit because of the possibility to switch to commercial alirocumab.
    End point type
    Secondary
    End point timeframe
    Parent Baseline, Weeks 48, 96, 144, and 168
    End point values
    Alirocumab: All Subjects Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects analysed
    974
    323
    651
    Units: percent change
    arithmetic mean (standard deviation)
        Week 48 (n= 913, 307, 606)
    -22.6 ± 97.6
    -15.0 ± 158.4
    -26.4 ± 40.2
        Week 96 (n= 713, 239, 474)
    -18.9 ± 146.9
    -13.9 ± 171.7
    -21.4 ± 132.7
        Week 144 (n= 198, 69, 129)
    -28.5 ± 34.3
    -20.1 ± 46.1
    -33.0 ± 25.0
        Week 168 (n= 10, 4, 6)
    -29.6 ± 15.6
    -30.3 ± 18.2
    -29.2 ± 15.4
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Apolipoprotein-B (Apo-B) at Weeks 48, 96, 144, and 168

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    End point title
    Percent Change From Baseline in Apolipoprotein-B (Apo-B) at Weeks 48, 96, 144, and 168
    End point description
    Baseline here corresponds to the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717). Post-baseline on-treatment data was obtained from Week 8 onwards up to Week 168 in this study. mITT population. Here, “n” signifies subjects evaluable at specified time-points. This number decreased significantly with visit because of the possibility to switch to commercial alirocumab.
    End point type
    Secondary
    End point timeframe
    Parent Baseline, Weeks 48, 96, 144, and 168
    End point values
    Alirocumab: All Subjects Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects analysed
    974
    323
    651
    Units: percent change
    arithmetic mean (standard deviation)
        Week 48 (n= 915, 308, 607)
    -37.5 ± 22.9
    -36.9 ± 21.7
    -37.8 ± 23.4
        Week 96 (n= 713, 238, 475)
    -37.6 ± 22.3
    -36.9 ± 20.9
    -38.0 ± 22.9
        Week 144 (n= 198, 69, 129)
    -35.9 ± 21.2
    -33.9 ± 20.9
    -36.9 ± 21.3
        Week 168 (n= 10, 4, 6)
    -41.1 ± 16.5
    -38.0 ± 9.0
    -43.1 ± 20.7
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Weeks 48, 96, 144, and 168

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    End point title
    Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Weeks 48, 96, 144, and 168
    End point description
    Baseline here corresponds to the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717). Post-baseline on-treatment data was obtained from Week 8 onwards up to Week 168 in this study. mITT population. Here, “n” signifies subjects evaluable at specified time-points. This number decreased significantly with visit because of the possibility to switch to commercial alirocumab.
    End point type
    Secondary
    End point timeframe
    Parent Baseline, Weeks 48, 96, 144, and 168
    End point values
    Alirocumab: All Subjects Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects analysed
    974
    323
    651
    Units: percent change
    arithmetic mean (standard deviation)
        Week 48 (n= 915, 308, 607)
    5.7 ± 16.3
    5.6 ± 14.5
    5.8 ± 17.2
        Week 96 (n= 713, 238, 475)
    8.3 ± 14.5
    7.8 ± 15.4
    8.5 ± 14.1
        Week 144 (n= 198, 69, 129)
    10.6 ± 17.8
    11.2 ± 16.3
    10.2 ± 18.7
        Week 168 (n= 10, 4, 6)
    2.7 ± 13.2
    0.9 ± 19.3
    3.9 ± 9.3
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Apo B/Apo A-1 Ratio at Weeks 48, 96, 144, and 168

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    End point title
    Absolute Change From Baseline in Apo B/Apo A-1 Ratio at Weeks 48, 96, 144, and 168
    End point description
    Baseline here corresponds to the baseline in the parent study (EFC12492, R727-CL-1112, EFC12732 or LTS11717). Post-baseline on-treatment data was obtained from Week 8 onwards up to Week 168 in this study. mITT population. Here, “n” signifies subjects evaluable at specified time-points. This number decreased significantly with visit because of the possibility to switch to commercial alirocumab.
    End point type
    Secondary
    End point timeframe
    Parent Baseline, Weeks 48, 96, 144, and 168
    End point values
    Alirocumab: All Subjects Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W
    Number of subjects analysed
    974
    323
    651
    Units: ratio
    arithmetic mean (standard deviation)
        Week 48 (n= 915, 308, 607)
    -0.354 ± 0.286
    -0.340 ± 0.245
    -0.361 ± 0.304
        Week 96 (n= 713, 238, 475)
    -0.363 ± 0.256
    -0.340 ± 0.228
    -0.375 ± 0.268
        Week 144 (n= 198, 69, 129)
    -0.389 ± 0.379
    -0.342 ± 0.242
    -0.414 ± 0.433
        Week 168 (n= 10, 4, 6)
    -0.447 ± 0.238
    -0.370 ± 0.161
    -0.498 ± 0.280
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 176 post-treatment follow-up visit) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs and deaths are TEAEs that is AEs that developed/worsened during the ‘treatment-emergent period’ (the time from the first dose of alirocumab in this study up to the day of last dose of alirocumab received in this study + 70 days).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo to Alirocumab 75 or 150 mg Q2W
    Reporting group description
    Alirocumab 75 mg or 150 mg SC injection Q2W added to stable LMT for up to 168 weeks in subjects who received placebo in the parent studies. Subjects from parent study EFC12732 (NCT01617655) started with alirocumab 150 mg Q2W and subjects from parent studies EFC12492 (NCT01623115), R727-CL-1112 (NCT01709500) and LTS11717 (NCT01507831) started with alirocumab 75 mg Q2W. Alirocumab doses could be either up-titrated from 75 to 150 mg Q2W or down-titrated from 150 to 75 mg Q2W from Week 12 or maintained according to the investigator judgement and LDL-C values.

    Reporting group title
    Alirocumab to Alirocumab 75 or 150 mg Q2W
    Reporting group description
    Alirocumab 75 mg or 150 mg SC injection Q2W added to stable LMT for up to 168 additional weeks in subjects who received Alirocumab in the parent studies. Subjects from parent study EFC12732 (NCT01617655) started with alirocumab 150 mg Q2W and subjects from parent studies EFC12492 (NCT01623115), R727-CL-1112 (NCT01709500) and LTS11717 (NCT01507831) started with alirocumab 75 mg Q2W. Alirocumab doses could be either up-titrated from 75 to 150 mg Q2W or down-titrated from 150 to 75 mg Q2W from Week 12 or maintained according to the investigator judgement and LDL-C values.

    Reporting group title
    Alirocumab: All Subjects
    Reporting group description
    All subjects who received alirocumab/placebo in the parent studies and received alirocumab 75 mg or 150 mg SC injection Q2W added to stable LMT for up to 168 additional weeks in this study.

    Serious adverse events
    Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W Alirocumab: All Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    68 / 330 (20.61%)
    144 / 655 (21.98%)
    212 / 985 (21.52%)
         number of deaths (all causes)
    4
    7
    11
         number of deaths resulting from adverse events
    Vascular disorders
    Air Embolism
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic Aneurysm
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Aortic Dissection
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Hypertension
         subjects affected / exposed
    1 / 330 (0.30%)
    1 / 655 (0.15%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iliac Artery Occlusion
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intermittent Claudication
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant Hypertension
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurogenic Shock
         subjects affected / exposed
    1 / 330 (0.30%)
    1 / 655 (0.15%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral Artery Stenosis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma Gastric
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Adenocarcinoma Of Colon
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign Pancreatic Neoplasm
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder Transitional Cell Carcinoma Recurrent
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast Cancer
         subjects affected / exposed
    1 / 330 (0.30%)
    1 / 655 (0.15%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast Cancer Recurrent
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic Lymphocytic Leukaemia Stage 0
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon Adenoma
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon Cancer
         subjects affected / exposed
    1 / 330 (0.30%)
    1 / 655 (0.15%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon Cancer Metastatic
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Hodgkin's Disease
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive Lobular Breast Carcinoma
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal Papilloma
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lobular Breast Carcinoma In Situ
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung Adenocarcinoma
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphocytic Leukaemia
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic Glioma
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian Adenoma
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian Cancer Stage Iii
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Papillary Cystadenoma Lymphomatosum
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Phyllodes Tumour
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate Cancer Metastatic
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate Cancer Stage Ii
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal Cancer Metastatic
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salivary Gland Adenoma
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous Cell Carcinoma Of Skin
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    1 / 330 (0.30%)
    2 / 655 (0.31%)
    3 / 985 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Malaise
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    2 / 330 (0.61%)
    4 / 655 (0.61%)
    6 / 985 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden Cardiac Death
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Vascular Stent Occlusion
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol Withdrawal Syndrome
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alcoholism
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium Tremens
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressed Mood
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Major Depression
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Bartholin's Cyst
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    0 / 330 (0.00%)
    2 / 655 (0.31%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian Cyst
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine Polyp
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal Dysplasia
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Acetabulum Fracture
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alcohol Poisoning
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Animal Bite
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthropod Bite
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Valve Replacement Complication
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intentional Overdose
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament Sprain
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple Injuries
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle Rupture
         subjects affected / exposed
    1 / 330 (0.30%)
    1 / 655 (0.15%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post Procedural Haemorrhage
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural Haemorrhage
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pubis Fracture
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sternal Fracture
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid Haemorrhage
         subjects affected / exposed
    0 / 330 (0.00%)
    2 / 655 (0.31%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Subdural Haematoma
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon Rupture
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thermal Burn
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic Vertebral Fracture
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper Limb Fracture
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular Bypass Dysfunction
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular Graft Thrombosis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound Dehiscence
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anticoagulation Drug Level Above Therapeutic
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heart Rate Irregular
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight Decreased
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    2 / 330 (0.61%)
    4 / 655 (0.61%)
    6 / 985 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Angina Pectoris
         subjects affected / exposed
    6 / 330 (1.82%)
    8 / 655 (1.22%)
    14 / 985 (1.42%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 8
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    4 / 330 (1.21%)
    5 / 655 (0.76%)
    9 / 985 (0.91%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic Valve Disease
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic Valve Disease Mixed
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic Valve Stenosis
         subjects affected / exposed
    2 / 330 (0.61%)
    1 / 655 (0.15%)
    3 / 985 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis Coronary Artery
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 330 (0.30%)
    3 / 655 (0.46%)
    4 / 985 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    2 / 330 (0.61%)
    2 / 655 (0.31%)
    4 / 985 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    Cardiac Failure Congestive
         subjects affected / exposed
    3 / 330 (0.91%)
    1 / 655 (0.15%)
    4 / 985 (0.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    2 / 330 (0.61%)
    4 / 655 (0.61%)
    6 / 985 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Occlusion
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Stenosis
         subjects affected / exposed
    3 / 330 (0.91%)
    3 / 655 (0.46%)
    6 / 985 (0.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Thrombosis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Cardiomyopathy
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral Valve Incompetence
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral Valve Stenosis
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    2 / 330 (0.61%)
    3 / 655 (0.46%)
    5 / 985 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Pericarditis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prinzmetal Angina
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    1 / 330 (0.30%)
    1 / 655 (0.15%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular Dysfunction
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular Tachycardia
         subjects affected / exposed
    1 / 330 (0.30%)
    3 / 655 (0.46%)
    4 / 985 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hereditary Non-Polyposis Colorectal Cancer Syndrome
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Pulmonary Oedema
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 330 (0.00%)
    2 / 655 (0.31%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 330 (0.00%)
    2 / 655 (0.31%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Hypertension
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic Anaemia
         subjects affected / exposed
    1 / 330 (0.30%)
    1 / 655 (0.15%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    2 / 330 (0.61%)
    0 / 655 (0.00%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid Arteriosclerosis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical Radiculopathy
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolic Cerebral Infarction
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Focal Dyscognitive Seizures
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    0 / 330 (0.00%)
    2 / 655 (0.31%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Normal Pressure Hydrocephalus
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 330 (0.30%)
    1 / 655 (0.15%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sensory Loss
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 330 (0.30%)
    6 / 655 (0.92%)
    7 / 985 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxic Encephalopathy
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 330 (0.00%)
    6 / 655 (0.92%)
    6 / 985 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular Dementia
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Corneal Decompensation
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 330 (0.00%)
    2 / 655 (0.31%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Open Angle Glaucoma
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Optic Ischaemic Neuropathy
         subjects affected / exposed
    1 / 330 (0.30%)
    1 / 655 (0.15%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal Detachment
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal Tear
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal Vein Occlusion
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Acute Vestibular Syndrome
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo Positional
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Hernia
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Barrett's Oesophagus
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis Ischaemic
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum Intestinal
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric Polyps
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer Haemorrhage
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis Haemorrhagic
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hiatus Hernia
         subjects affected / exposed
    1 / 330 (0.30%)
    1 / 655 (0.15%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    0 / 330 (0.00%)
    2 / 655 (0.31%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Internal Hernia
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Chronic
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 330 (0.00%)
    2 / 655 (0.31%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal Ulcer Haemorrhage
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    0 / 330 (0.00%)
    2 / 655 (0.31%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical Hernia
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    2 / 330 (0.61%)
    2 / 655 (0.31%)
    4 / 985 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 330 (0.30%)
    3 / 655 (0.46%)
    4 / 985 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Pain
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Incontinence
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 330 (0.30%)
    1 / 655 (0.15%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic Steatosis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular Injury
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Hypersensitivity Vasculitis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash Generalised
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Acquired Claw Toe
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 330 (0.30%)
    1 / 655 (0.15%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exostosis
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture Pain
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    1 / 330 (0.30%)
    5 / 655 (0.76%)
    6 / 985 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck Pain
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 330 (0.61%)
    5 / 655 (0.76%)
    7 / 985 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain In Extremity
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid Arthritis
         subjects affected / exposed
    1 / 330 (0.30%)
    1 / 655 (0.15%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator Cuff Syndrome
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal Column Stenosis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 Diabetes Mellitus
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 330 (0.00%)
    2 / 655 (0.31%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter Site Infection
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 330 (0.00%)
    3 / 655 (0.46%)
    3 / 985 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Corneal Abscess
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis Bacterial
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device Related Sepsis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    1 / 330 (0.30%)
    1 / 655 (0.15%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma Infection
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    0 / 330 (0.00%)
    2 / 655 (0.31%)
    2 / 985 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritoneal Abscess
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 330 (0.61%)
    3 / 655 (0.46%)
    5 / 985 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Pneumonia Pseudomonal
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative Abscess
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative Wound Infection
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stitch Abscess
         subjects affected / exposed
    1 / 330 (0.30%)
    0 / 655 (0.00%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral Myocarditis
         subjects affected / exposed
    0 / 330 (0.00%)
    1 / 655 (0.15%)
    1 / 985 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo to Alirocumab 75 or 150 mg Q2W Alirocumab to Alirocumab 75 or 150 mg Q2W Alirocumab: All Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    183 / 330 (55.45%)
    366 / 655 (55.88%)
    549 / 985 (55.74%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    13 / 330 (3.94%)
    37 / 655 (5.65%)
    50 / 985 (5.08%)
         occurrences all number
    13
    39
    52
    General disorders and administration site conditions
    Influenza Like Illness
         subjects affected / exposed
    12 / 330 (3.64%)
    40 / 655 (6.11%)
    52 / 985 (5.28%)
         occurrences all number
    17
    48
    65
    Injection Site Reaction
         subjects affected / exposed
    26 / 330 (7.88%)
    28 / 655 (4.27%)
    54 / 985 (5.48%)
         occurrences all number
    66
    148
    214
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    19 / 330 (5.76%)
    43 / 655 (6.56%)
    62 / 985 (6.29%)
         occurrences all number
    21
    52
    73
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    34 / 330 (10.30%)
    53 / 655 (8.09%)
    87 / 985 (8.83%)
         occurrences all number
    37
    59
    96
    Back Pain
         subjects affected / exposed
    26 / 330 (7.88%)
    56 / 655 (8.55%)
    82 / 985 (8.32%)
         occurrences all number
    29
    65
    94
    Myalgia
         subjects affected / exposed
    15 / 330 (4.55%)
    44 / 655 (6.72%)
    59 / 985 (5.99%)
         occurrences all number
    18
    47
    65
    Pain In Extremity
         subjects affected / exposed
    18 / 330 (5.45%)
    31 / 655 (4.73%)
    49 / 985 (4.97%)
         occurrences all number
    18
    38
    56
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    19 / 330 (5.76%)
    41 / 655 (6.26%)
    60 / 985 (6.09%)
         occurrences all number
    23
    45
    68
    Influenza
         subjects affected / exposed
    34 / 330 (10.30%)
    61 / 655 (9.31%)
    95 / 985 (9.64%)
         occurrences all number
    40
    73
    113
    Upper Respiratory Tract Infection
         subjects affected / exposed
    31 / 330 (9.39%)
    71 / 655 (10.84%)
    102 / 985 (10.36%)
         occurrences all number
    44
    104
    148
    Urinary Tract Infection
         subjects affected / exposed
    21 / 330 (6.36%)
    28 / 655 (4.27%)
    49 / 985 (4.97%)
         occurrences all number
    28
    37
    65
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    51 / 330 (15.45%)
    93 / 655 (14.20%)
    144 / 985 (14.62%)
         occurrences all number
    70
    123
    193

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jul 2014
    1. Clarified inclusion criterion I01. 2. Updated language on cardiovascular events to be reported to the CEC for adjudication and included a clarification on cerebrovascular events. 3. Updated language on collection of partner pregnancy as per other protocol in the ODYSSEY phase 3 program. 4. Categorization of AEs (updated language on how to record injection site reactions that were not related to IMP).
    10 Jul 2015
    1. Prolongation of the study duration by 1 year to allow patients in most countries to benefit from commercial alirocumab. 2. Removal of the Clinical Events Committee (cardiovascular events adjudication): since this study was a non-comparative study, there were no purposes in having the CV events adjudicated, and thus the process was discontinued. 3. Termination of Steering Committee activities on 31 December 2015 since most of the phase 3a studies were completed. 4. Possibility to add an Interim analysis in order to either be able to answer potential Health Authorities requests or to provide analyses for scientific purposes. 5. Removal of the specific ADA monitoring after the follow-up visit. 6. Modification of personal data collection: collection of racial origin as this information was needed for creatinine clearance calculation.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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