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    Clinical Trial Results:
    A Double-Blind, Placebo Controlled, Multicenter Study to Assess the Effect of Evolocumab on Cognitive Function in Patients with Clinically Evident Cardiovascular Disease and Receiving Statin Background Lipid Lowering Therapy: A Study for Subjects Enrolled in the FOURIER (Study 20110118) Trial

    Summary
    EudraCT number
    		 2014-001976-75
    Trial protocol
    		 SE   GR   IT   FI   EE   SK   LV   DE   LT   CZ   PT   BE   HU   DK   ES   NL  
    Global end of trial date
    11 Nov 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    19 Jan 2018
    First version publication date
    26 Nov 2017
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    20130385
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02207634
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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
    20 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate change over time in executive function, as assessed by the Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Working Memory (SWM) strategy index of executive function, in subjects receiving statin therapy in combination with evolocumab, compared with subjects receiving statin therapy in combination with placebo.
    Protection of trial subjects
    This study was conducted in accordance with International Council on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. Essential documents will be retained in accordance with ICH GCP. The study and all amendments were reviewed by an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) at each center. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures.
    Background therapy
    		 Participants were required to be on a stable, high- to moderate-intensity statin background therapy consisting of an effective statin dose, ie, at least atorvastatin 20 mg daily or equivalent, and where locally approved, highly effective statin therapy (defined as at least atorvastatin 40 mg daily or equivalent) was recommended.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Sep 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 28
    Country: Number of subjects enrolled
    Japan: 39
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    New Zealand: 16
    Country: Number of subjects enrolled
    South Africa: 51
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Czech Republic: 161
    Country: Number of subjects enrolled
    Denmark: 44
    Country: Number of subjects enrolled
    Estonia: 35
    Country: Number of subjects enrolled
    Finland: 54
    Country: Number of subjects enrolled
    France: 33
    Country: Number of subjects enrolled
    Germany: 75
    Country: Number of subjects enrolled
    Greece: 5
    Country: Number of subjects enrolled
    Hungary: 93
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Latvia: 33
    Country: Number of subjects enrolled
    Lithuania: 7
    Country: Number of subjects enrolled
    Netherlands: 23
    Country: Number of subjects enrolled
    Norway: 16
    Country: Number of subjects enrolled
    Poland: 254
    Country: Number of subjects enrolled
    Portugal: 18
    Country: Number of subjects enrolled
    Russian Federation: 209
    Country: Number of subjects enrolled
    Slovakia: 80
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Sweden: 15
    Country: Number of subjects enrolled
    Turkey: 31
    Country: Number of subjects enrolled
    United Kingdom: 118
    Country: Number of subjects enrolled
    Canada: 63
    Country: Number of subjects enrolled
    United States: 416
    Worldwide total number of subjects
    1974
    EEA total number of subjects
    1119
    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)
    1088
    From 65 to 84 years
    883
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants enrolled in Study 20110118 (FOURIER; NCT01764633) at select sites in select countries (based on study start-up timelines) were invited to participate in this cognitive function study. Participants were enrolled at 340 centers in 29 countries in Europe, North America, and Asia Pacific from September 2014 to July 2015.

    Pre-assignment
    Screening details
    		 There was no separate randomization in this study; each participant received their assigned treatment per Protocol 20110118. Data were analyzed according to Study 20110118 randomized treatment arm.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo subcutaneous injections either once every 2 weeks (Q2W) or once a month (QM) according to their own preference. Participants continued with their background statin therapy during the course of the study.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen.

    Arm title
    		 Evolocumab
    Arm description
    		 Participants received evolocumab 140 mg Q2W or 420 mg QM subcutaneous injections according to their own preference. Participants continued with their background statin therapy during the course of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evolocumab
    Investigational medicinal product code
    AMG 145
    Other name
    Repatha
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen.

    Number of subjects in period 1
    		Placebo Evolocumab
    Started
    990
    984
    Received Treatment
    990
    983
    Completed
    968
    953
    Not completed
    22
    31
         Consent withdrawn by subject
    21
    31
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneous injections either once every 2 weeks (Q2W) or once a month (QM) according to their own preference. Participants continued with their background statin therapy during the course of the study.

    Reporting group title
    Evolocumab
    Reporting group description
    		 Participants received evolocumab 140 mg Q2W or 420 mg QM subcutaneous injections according to their own preference. Participants continued with their background statin therapy during the course of the study.

    Reporting group values
    		 Placebo Evolocumab Total
    Number of subjects
    		 990 984 1974
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.7 ( 8.7 ) 62.9 ( 8.7 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 274 269 543
        Male
    		 716 715 1431
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 2 1 3
        Asian
    		 28 31 59
        Black or African American
    		 32 28 60
        Native Hawaiian or Other Pacific Islander
    		 0 3 3
        White
    		 910 908 1818
        Multiple
    		 1 1 2
        Other
    		 17 12 29
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    		 14 9 23
        Not Hispanic/Latino
    		 976 975 1951
    Spatial Working Memory (SWM) Strategy Index of Executive Function Raw Score
    CANTAB is a series of computerized tests to assess cognitive function. The SWM test assesses the cognitive domain of executive function (high-level thinking and decision making). Patients search for colored tokens hidden inside boxes on the screen. Tokens were never hidden inside the same box twice, so patients must not return to a box where a token was already found. The SWM strategy index of executive function represents the number of times a patient began a search with a different box. A high score represents an inefficient use of strategy and planning. The raw score ranges from 4 to 28.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 17.8 ( 3.4 ) 17.8 ( 3.5 ) -
    Spatial Working Memory (SWM) Strategy Index of Executive Function Z Score
    The CANTAB SWM test assesses the cognitive domain of executive function (high-level thinking and decision making). Patients search for colored tokens hidden inside boxes on the screen. Tokens were never hidden inside the same box twice, so patients must not return to a box where a token was already found. The SWM strategy index of executive function represents the number of times a patient began a search with a different box. The Z score represents the standardized measure of how far an individual deviates from the study cohort average at baseline. A higher Z score reflects better performance.
    Units: Z score
        arithmetic mean (standard deviation)
    		 -0.0106 ( 0.9910 ) 0.0166 ( 1.0066 ) -
    Spatial Working Memory Between Errors Raw Score
    The CANTAB Spatial Working Memory (SWM) between-errors score test assesses the cognitive domain of working memory (holding material in mind while that material is being actively processed). Patients search for colored tokens hidden inside boxes on the screen. Tokens were never hidden inside the same box twice, so patients must not return to a box where a token was already found. The SWM between-errors score is the number of times that a patient revisited a box in which a token had previously been found. A lower score indicates better performance. The raw score ranges from 0 to 279.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 21.0 ( 10.6 ) 20.9 ( 10.2 ) -
    Paired Associates Learning (PAL) Total Errors Adjusted Raw Score
    The CANTAB PAL test assesses memory function (storing/retrieving information by associating an event with a time and place). Boxes on the screen open in turn to reveal a number of patterns. After all the boxes were opened, each pattern was shown in a randomized order and the patient asked to touch the box where they think the pattern was hidden. The PAL total errors adjusted score is the number of errors made plus an adjustment for the estimated number of errors the patient would have made on any stages not reached. A lower score indicates better performance. The raw score ranges from 0 to 70.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 25.2 ( 18.4 ) 26.5 ( 19.3 ) -
    Spatial Working Memory Between Errors Z Score
    The CANTAB Spatial Working Memory (SWM) between-errors score test assesses the cognitive domain of working memory (holding material in mind while that material is being actively processed). Patients search for colored tokens hidden inside boxes on the screen. Tokens were never hidden inside the same box twice, so patients must not return to a box where a token was already found. The SWM between-errors score is the number of times a patient revisited a box in which a token had already been found. A higher Z score reflects better performance.
    Units: Z score
        arithmetic mean (standard deviation)
    		 -0.0130 ( 1.0075 ) 0.0024 ( 0.9675 ) -
    Paired Associates Learning Total Errors Adjusted Z Score
    The CANTAB PAL test assesses memory function (storing/retrieving information by associating an event with a time and place). Boxes on the screen open in turn to reveal a number of patterns. After all the boxes have been opened, each pattern was shown in a randomized order and the patient asked to touch the box where they think each pattern was hidden. The PAL total errors adjusted is the number of errors committed plus an adjustment for the estimated number of errors the patient would have made on any stages not reached. Higher Z scores indicate better performance.
    Units: Z score
        arithmetic mean (standard deviation)
    		 0.0442 ( 0.9834 ) -0.0272 ( 1.0294 ) -
    Reaction Time Median 5-Choice Reaction Time Raw Score
    The CANTAB Reaction Time (RTI) test assessed psychomotor speed (detecting and responding to a stimulus). Participants held down a button until a spot appeared in 1 of 5 circles on the screen. As soon as possible after the spot flashed up, the patient lifted their finger from the button and touched the circle in which the spot appeared. The RTI median 5-choice reaction time was the median duration between the onset of the stimulus and the release of the button. A lower score indicates better performance. The raw score ranges from 100 to 5100 msec.
    Units: msec
        arithmetic mean (standard deviation)
    		 355.10 ( 77.60 ) 356.74 ( 65.01 ) -
    Reaction Time Median 5-Choice Reaction Time Z Score
    The CANTAB Reaction Time (RTI) test assessed psychomotor speed (detecting and responding to a stimulus). Participants held down a button until a spot appeared in 1 of 5 circles on the screen. As soon as possible after the spot flashed up, the patient moved their finger from the button to the circle in which the spot appeared. The RTI median 5-choice reaction time is the median duration between the onset of the stimulus and the release of the button. A higher Z score reflects better performance.
    Units: Z score
        arithmetic mean (standard deviation)
    		 -0.0271 ( 1.0829 ) -0.0500 ( 0.9072 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneous injections either once every 2 weeks (Q2W) or once a month (QM) according to their own preference. Participants continued with their background statin therapy during the course of the study.

    Reporting group title
    Evolocumab
    Reporting group description
    		 Participants received evolocumab 140 mg Q2W or 420 mg QM subcutaneous injections according to their own preference. Participants continued with their background statin therapy during the course of the study.

    Primary: Mean Change from Baseline in Spatial Working Memory Strategy Index of Executive Function (6-8 boxes) Z Score

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    End point title
    		 Mean Change from Baseline in Spatial Working Memory Strategy Index of Executive Function (6-8 boxes) Z Score
    End point description
    Assessments were performed with the Cambridge Neuropsychological Test Automated Battery (CANTAB), a language-independent battery of computerized tests that is used to assess cognitive function. The Spatial Working Memory (SWM) test assesses the cognitive domain of executive function (high-level thinking and decision making). Patients search for colored tokens hidden inside boxes on the screen by touching them. The critical instruction is that once a token has been found inside a box, there will never be a token hidden inside that box again, so patients must not return to a box where a token has been found. The SWM strategy index of executive function represented the number of times a subject began a search with a different box. The Z score represents the standardized measure of how far an individual subject deviates from the study cohort average at baseline. A higher Z score reflects better performance. The mean change from baseline averaged across all the visits is reported.
    End point type
    Primary
    End point timeframe
    Assessments were conducted at Baseline and at weeks 24, 48, 96, 144 and end of study visit (median time on study was 19.4 months).
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    616 [1]
    586 [2]
    Units: Z score
        least squares mean (confidence interval 95%)
    0.1206 (0.0535 to 0.1877)
    0.1134 (0.0449 to 0.1820)
    Notes
    [1] - Cognitive function assessments after an on-study stroke event were excluded from the analysis.
    [2] - Cognitive function assessments after an on-study stroke event were excluded from the analysis.
    Statistical analysis title
    		 Non-inferiority Analysis
    Statistical analysis description
    A repeated measures mixed-effect linear model was used to estimate treatment difference (placebo - evolocumab) in change from baseline and associated 95% confidence intervals (CI). The model included stratification factors for Study 20110118 (final screening low-density lipoprotein cholesterol [LDL-C] and geographical region), age, education level, baseline SWM strategy index Z score, treatment group, visit, and treatment by visit interaction.
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    1202
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    0.0072
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0664
         upper limit
    		 0.0808
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0375
    Notes
    [3] - The non-inferiority margin was 0.19, calculated as 20% of the observed common standard deviation, which was estimated from observations in the placebo group by a repeated measured mixed-effect linear model with visit as a covariate. If the upper bound of the 95% CI for the difference between the placebo and evolocumab group in mean change from baseline for Z score averaged across the visits was less than the non-inferiority margin non-inferiority criteria were met.

    Secondary: Mean Change from Baseline in Spatial Working Memory (SWM) Between-errors Z Score

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    End point title
    		 Mean Change from Baseline in Spatial Working Memory (SWM) Between-errors Z Score
    End point description
    Assessments were performed with the CANTAB, a language-independent battery of computerized tests that is used to assess cognitive function. The Spatial Working Memory (SWM) between-errors test assesses the cognitive domain of working memory (holding material in mind while that material is being actively processed). Patients search for colored tokens hidden inside boxes on the screen by touching them. The critical instruction is that once a token has been found inside a box, there will never be a token hidden inside that box again, so patients must not return to a box where a token has been found. The SWM between-errors score is the number of times that a patient revisited a box in which a token had previously been found. The Z score represents the standardized measure of how far an individual participant deviates from the study cohort average at baseline. A higher Z score reflects better performance. The mean change from baseline averaged across all the visits is reported.
    End point type
    Secondary
    End point timeframe
    Assessments were conducted at Baseline and at weeks 24, 48, 96, 144 and end of study visit (median time on study was 19.4 months).
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    616 [4]
    586 [5]
    Units: Z score
        least squares mean (confidence interval 95%)
    0.1024 (0.0373 to 0.1675)
    0.0691 (0.0026 to 0.1355)
    Notes
    [4] - Cognitive function assessments after an on-study stroke event were excluded from the analysis.
    [5] - Cognitive function assessments after an on-study stroke event were excluded from the analysis.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    A repeated measures mixed-effect linear model was used to estimate treatment difference (placebo - evolocumab) in change from baseline and associated 95% confidence intervals (CI). The model included stratification factors for Study 20110118 (final screening LDL-C and geographical region), age, education level, baseline SWM between-errors Z score, treatment group, visit, and treatment by visit interaction.
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    1202
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    0.0333
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0378
         upper limit
    		 0.1045
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0363

    Secondary: Mean Change from Baseline in Paired Associated Learning (PAL) Total Errors Adjusted Z Score

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    End point title
    		 Mean Change from Baseline in Paired Associated Learning (PAL) Total Errors Adjusted Z Score
    End point description
    The CANTAB PAL test assesses visuospatial episodic memory (storing/retrieving information by associating an event with a time and place). Boxes on the screen opened up one at a time to reveal a number of patterns. Participants were asked to remember the location of each pattern. After all the boxes had been opened, each pattern was then shown in the center of the screen in a randomized order, and the patient should touch the box where they think each pattern was hidden. The PAL total errors adjusted comprised the number of errors committed by a patient plus an adjustment for the estimated number of errors the patient would have made on any stages that were not reached. Z score represents the standardized measure of how far an individual patient deviates from the study cohort average at baseline. A higher Z score indicated better performance. The mean change from baseline averaged across all the visits is reported.
    End point type
    Secondary
    End point timeframe
    Assessments were conducted at Baseline and at weeks 24, 48, 96, 144 and end of study visit (median time on study was 19.4 months).
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    615 [6]
    585 [7]
    Units: Z score
        least squares mean (confidence interval 95%)
    0.1098 (0.0511 to 0.1686)
    0.0873 (0.0273 to 0.1472)
    Notes
    [6] - Cognitive function assessments after an on-study stroke event were excluded from the analysis.
    [7] - Cognitive function assessments after an on-study stroke event were excluded from the analysis.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    A repeated measures mixed-effect linear model was used to estimate treatment difference (placebo - evolocumab) in change from baseline and associated 95% confidence intervals (CI). The model included stratification factors for Study 20110118 (final screening LDL-C and geographical region), age, education level, baseline PAL total errors adjusted Z score, treatment group, visit, and treatment by visit interaction.
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    1200
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    0.0226
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0422
         upper limit
    		 0.0873
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.033

    Secondary: Mean Change from Baseline in Reaction Time (RTI) Median 5-choice Reaction Time Z score

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    End point title
    		 Mean Change from Baseline in Reaction Time (RTI) Median 5-choice Reaction Time Z score
    End point description
    Assessments were performed with the CANTAB, a language-independent battery of computerized tests that is used to assess cognitive function. The Reaction Time (RTI) test assessed the cognitive domain of psychomotor speed (detecting and responding to a stimulus). Participants held down a button until a spot appeared in 1 of 5 circles on the screen. As soon as possible after the spot flashed up, the patient lifted their finger from the button and touched the circle in which the spot appeared. The RTI median 5-choice reaction time was the median duration between the onset of the stimulus and the release of the button. Z score represents the standardized measure of how far an individual participant deviates from the study cohort average at baseline. A higher Z score reflects better performance. The mean change from baseline averaged across all the visits is reported.
    End point type
    Secondary
    End point timeframe
    Assessments were conducted at Baseline and at weeks 24, 48, 96, 144 and end of study visit (median time on study was 19.4 months).
    End point values
    		 Placebo Evolocumab
    Number of subjects analysed
    611 [8]
    584 [9]
    Units: Z score
        least squares mean (confidence interval 95%)
    0.0153 (-0.0529 to 0.0834)
    -0.0575 (-0.1270 to 0.0121)
    Notes
    [8] - Cognitive function assessments after an on-study stroke event were excluded from the analysis.
    [9] - Cognitive function assessments after an on-study stroke event were excluded from the analysis.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    A repeated measures mixed-effect linear model was used to estimate treatment difference ( placebo - evolocumab) in change from baseline and associated 95% confidence intervals (CI). The model included stratification factors for Study 20110118 (final screening LDL-C and geographical region), age, education level, baseline RTI median 5-choice reaction time Z score, treatment group, visit, and treatment by visit interaction.
    Comparison groups
    Placebo v Evolocumab
    Number of subjects included in analysis
    1195
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    0.0727
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0022
         upper limit
    		 0.1477
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0382

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug to the end of study. The median duration of follow-up was 19.4 months.
    Adverse event reporting additional description
    Although there was no separate safety data collection, recording or reporting planned in this study, an ad-hoc analysis of safety data collected in Study 20110118 was conducted for subjects in this Study and is reported here. Deaths by any cause were collected as adjudicated efficacy endpoints and reported as a secondary endpoint in Study 20110118.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Evolocumab
    Reporting group description
    		 Participants received evolocumab 140 mg Q2W or 420 mg QM subcutaneous injections according to their own preference. Participants continued with their background statin therapy during the course of the study.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneous injections either once every 2 weeks (Q2W) or once a month (QM) according to their own preference. Participants continued with their background statin therapy during the course of the study.

    Serious adverse events
    		 Evolocumab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    212 / 983 (21.57%)
    204 / 990 (20.61%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign pancreatic neoplasm
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    2 / 983 (0.20%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma stage III
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    0 / 983 (0.00%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cancer stage 0
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lip and/or oral cavity cancer stage III
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    2 / 983 (0.20%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma metastatic
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 983 (0.10%)
    4 / 990 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung squamous cell carcinoma stage III
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma benign
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoproliferative disorder
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer metastatic
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsil cancer
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    1 / 983 (0.10%)
    4 / 990 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm rupture
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 983 (0.20%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    7 / 983 (0.71%)
    5 / 990 (0.51%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 983 (0.31%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iliac artery occlusion
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leriche syndrome
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    2 / 983 (0.20%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    10 / 983 (1.02%)
    5 / 990 (0.51%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    2 / 983 (0.20%)
    4 / 990 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    6 / 983 (0.61%)
    4 / 990 (0.40%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian artery stenosis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 983 (0.10%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Fracture treatment
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric banding reversal
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 983 (0.20%)
    4 / 990 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    6 / 983 (0.61%)
    12 / 990 (1.21%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue inflammation
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 983 (0.10%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 983 (0.10%)
    3 / 990 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma-chronic obstructive pulmonary disease overlap syndrome
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    4 / 983 (0.41%)
    5 / 990 (0.51%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 983 (0.20%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    0 / 983 (0.00%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 983 (0.00%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriogram coronary
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 983 (0.00%)
    3 / 990 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood potassium increased
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 983 (0.20%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial necrosis marker increased
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid function test abnormal
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 983 (0.00%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial bypass occlusion
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    2 / 983 (0.20%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery restenosis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dislocation of sternum
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye injury
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 983 (0.20%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial reocclusion
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery restenosis
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoconiosis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis chemical
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post concussion syndrome
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural constipation
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural swelling
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column injury
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Intracranial lipoma
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    15 / 983 (1.53%)
    16 / 990 (1.62%)
         occurrences causally related to treatment / all
    0 / 18
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    11 / 983 (1.12%)
    15 / 990 (1.52%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 983 (0.00%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    13 / 983 (1.32%)
    7 / 990 (0.71%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 983 (0.00%)
    3 / 990 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block left
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 983 (0.10%)
    4 / 990 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    2 / 983 (0.20%)
    4 / 990 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    4 / 983 (0.41%)
    5 / 990 (0.51%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 983 (0.20%)
    3 / 990 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dressler's syndrome
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart alternation
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve stenosis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    3 / 983 (0.31%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 983 (0.10%)
    3 / 990 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Arachnoid cyst
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery disease
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    6 / 983 (0.61%)
    5 / 990 (0.51%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical myelopathy
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 983 (0.20%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 983 (0.00%)
    3 / 990 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meralgia paraesthetica
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinsonism
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 983 (0.00%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    3 / 983 (0.31%)
    4 / 990 (0.40%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 983 (0.20%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 983 (0.20%)
    6 / 990 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spleen disorder
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 983 (0.10%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Iridocyclitis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 983 (0.00%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Strabismus
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 983 (0.20%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    2 / 983 (0.20%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coeliac artery stenosis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric disorder
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 983 (0.20%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal polyp haemorrhage
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 983 (0.10%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    3 / 983 (0.31%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric artery stenosis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic cyst
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 983 (0.00%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reflux gastritis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    2 / 983 (0.20%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis obstructive
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    2 / 983 (0.20%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermal cyst
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    1 / 983 (0.10%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eczema nummular
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperhidrosis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    2 / 983 (0.20%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 983 (0.20%)
    6 / 990 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urethral
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 983 (0.00%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    0 / 983 (0.00%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 983 (0.20%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 983 (0.00%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 983 (0.00%)
    5 / 990 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exostosis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    2 / 983 (0.20%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 983 (0.10%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia intercostal
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    3 / 983 (0.31%)
    3 / 990 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in jaw
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendiceal abscess
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 983 (0.00%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burkholderia cepacia complex infection
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 983 (0.10%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 983 (0.10%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 983 (0.00%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    3 / 983 (0.31%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    10 / 983 (1.02%)
    7 / 990 (0.71%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    2 / 983 (0.20%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 983 (0.00%)
    4 / 990 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 983 (0.20%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 983 (0.00%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    2 / 983 (0.20%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    2 / 983 (0.20%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 983 (0.00%)
    1 / 990 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 983 (0.10%)
    2 / 990 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 983 (0.10%)
    0 / 990 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Evolocumab Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    272 / 983 (27.67%)
    257 / 990 (25.96%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    61 / 983 (6.21%)
    66 / 990 (6.67%)
         occurrences all number
    62
    75
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    58 / 983 (5.90%)
    36 / 990 (3.64%)
         occurrences all number
    62
    39
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    101 / 983 (10.27%)
    74 / 990 (7.47%)
         occurrences all number
    133
    85
    Upper respiratory tract infection
         subjects affected / exposed
    53 / 983 (5.39%)
    63 / 990 (6.36%)
         occurrences all number
    61
    70
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    45 / 983 (4.58%)
    59 / 990 (5.96%)
         occurrences all number
    48
    65

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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