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    Clinical Trial Results:
    A placebo-controlled, double-blind, randomized trial to compare the effect of different doses of inclisiran given as single or multiple subcutaneous injections in subjects with high cardiovascular risk and elevated LDL-C.

    Summary
    EudraCT number
    2015-003772-74
    Trial protocol
    GB   DE   NL  
    Global end of trial date
    07 Jun 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Feb 2019
    First version publication date
    20 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MDCO-PCS-15-01
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02597127
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Trial Name: ORION-1
    Sponsors
    Sponsor organisation name
    The Medicines Company
    Sponsor organisation address
    8 Sylvan Way, Parsippany, United States, NJ 07054
    Public contact
    Global Health Science Center, The Medicines Company, +1 9732906000, medical.information@themedco.com
    Scientific contact
    Global Health Science Center, The Medicines Company, +1 9732906000, medical.information@themedco.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
    07 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of inclisiran treatment on low-density lipoprotein cholesterol (LDL-C) levels at Day 180.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Dec 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    5 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 71
    Country: Number of subjects enrolled
    United States: 84
    Country: Number of subjects enrolled
    Netherlands: 169
    Country: Number of subjects enrolled
    United Kingdom: 86
    Country: Number of subjects enrolled
    Germany: 91
    Worldwide total number of subjects
    501
    EEA total number of subjects
    346
    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)
    253
    From 65 to 84 years
    245
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    This study included male or female participants ≥18 years of age with a history of atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents or a >20% ten-year risk of a cardiovascular (CV) event assessed by Framingham Risk Score or equivalent and receiving maximum-tolerated lipid-lowering therapy.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject
    Blinding implementation details
    The study drug was blinded within each injection regimen: either 1 or 2 injections on Day 1 or a single injection on Day 1 and on Day 90. Study drug was prepared by the unblinded hospital pharmacist and was dispensed in a blinded syringe as randomized by the interactive web response system. Blinding was achieved by placing an over label on each unique syringe dispensed by the pharmacist, masking the color of the solution within because inclisiran could be visually distinguishable from placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Single Dose
    Arm description
    Participants received 1 of 3 different doses (200 milligrams [mg], 300 mg, or 500 mg) of inclisiran or matching placebo on Day 1. These 4 groups received no further study drug or placebo.
    Arm type
    Experimental

    Investigational medicinal product name
    Inclisiran
    Investigational medicinal product code
    Other name
    ALN-PCSSC
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All eligible participants were randomized and received their first subcutaneous (SC) injection of inclisiran (200 mg, 300 mg, or 500 mg) on Day 1. The 500-mg dose was administered as 2 injections, 1 of 300 mg (1.5 milliliters [mL]) and 1 of 200 mg (1.0 mL) in 2 different injection sites. A volume of 1.5 mL was the maximum injection volume for a single injection site.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Saline (sterile, normal, 0.9%)
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo was administered as an SC injection in an amount matched to the doses within the Single Dose Arm.

    Arm title
    Double Dose
    Arm description
    Participants received 1 of 3 different doses (100 mg, 200 mg, or 300 mg) of inclisiran or matching placebo on Day 1. These 4 groups then received a second dose on Day 90.
    Arm type
    Experimental

    Investigational medicinal product name
    Inclisiran
    Investigational medicinal product code
    Other name
    ALN-PCSSC
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All eligible participants were randomized and received their SC injections of inclisiran (100 mg, 200 mg, or 300 mg) on Days 1 and 90. A volume of 1.5 mL was the maximum injection volume for a single injection.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Saline (sterile, normal, 0.9%)
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo was administered as an SC injection in an amount matched to the doses within the Double Dose Arm.

    Number of subjects in period 1
    Single Dose Double Dose
    Started
    253
    248
    Completed
    236
    233
    Not completed
    17
    15
         Death
             1
             1
         Other
             4
             2
         Physician decision
             1
             1
         Adverse event, non-fatal
             3
             4
         Consent withdrawn by subject
             6
             7
         Lost to follow-up
             2
             -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Single Dose
    Reporting group description
    Participants received 1 of 3 different doses (200 milligrams [mg], 300 mg, or 500 mg) of inclisiran or matching placebo on Day 1. These 4 groups received no further study drug or placebo.

    Reporting group title
    Double Dose
    Reporting group description
    Participants received 1 of 3 different doses (100 mg, 200 mg, or 300 mg) of inclisiran or matching placebo on Day 1. These 4 groups then received a second dose on Day 90.

    Reporting group values
    Single Dose Double Dose Total
    Number of subjects
    253 248 501
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    129 124 253
        From 65-84 years
    123 122 245
        85 years and over
    1 2 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63 ± 11.9 63.6 ± 10 -
    Gender categorical
    Units: Subjects
        Female
    83 92 175
        Male
    170 156 326
    Race
    Units: Subjects
        American Indian or Alaska Native
    3 3 6
        Asian
    6 3 9
        Black or African
    10 8 18
        Native Hawaiian or Other Pacific Islander
    1 0 1
        White
    231 234 465
        Undisclosed
    2 0 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    15 14 29
        Not Hispanic or Latino
    238 234 472
    Subject analysis sets

    Subject analysis set title
    Intent-to-Treat (ITT) Population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All participants randomized into the trial. Treatment classification was based on the randomized treatment. This population was used to assess the randomness of treatment allocation.

    Subject analysis set title
    Modified Intent-to-Treat (mITT) Population
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    All randomized participants who received at least 1 dose of study drug and had both the baseline and the 180-day follow-up LDL-C assessment. Treatment classification was based on the randomized treatment. This was the primary population for analysis of the primary and secondary endpoints.

    Subject analysis set title
    Single Dose Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received an SC injection of placebo (0.9% saline) in amounts matched to the doses administered in the Single Dose Arm.

    Subject analysis set title
    Single Dose 200 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants in this group received a 200-mg SC injection of inclisiran on Day 1 of the study.

    Subject analysis set title
    Single Dose 300 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants in this group received a 300-mg SC injection of inclisiran on Day 1 of the study.

    Subject analysis set title
    Single Dose 500 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    On Day 1 of the study, participants in this group received a 500-mg dose of inclisiran as 2 injections, 1 of 300 mg and 1 of 200 mg.

    Subject analysis set title
    Double Dose Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received SC injections of placebo (0.9% saline) in amounts matched to the doses administered in the Double Dose Arm.

    Subject analysis set title
    Double Dose 100 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants in this group received their first 100-mg SC injection of inclisiran on Day 1 of the study. This was followed by a second injection on Day 90.

    Subject analysis set title
    Double Dose 200 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants in this group received their first 200-mg SC injection of inclisiran on Day 1 of the study. This was followed by a second injection on Day 90.

    Subject analysis set title
    Double Dose 300 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants in this group received their first 300-mg SC injection of inclisiran on Day 1 of the study. This was followed by a second injection on Day 90.

    Subject analysis set title
    Single and Double Dose Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis includes all participants in both the single dose and the double dose placebo groups.

    Subject analysis set title
    Single and Double Dose 200 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis includes all participants in both the single dose and the double dose 200 mg groups.

    Subject analysis set title
    Single and Double Dose 300 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis includes all participants in both the single dose and the double dose 300 mg groups.

    Subject analysis sets values
    Intent-to-Treat (ITT) Population Modified Intent-to-Treat (mITT) Population Single Dose Placebo Single Dose 200 mg Single Dose 300 mg Single Dose 500 mg Double Dose Placebo Double Dose 100 mg Double Dose 200 mg Double Dose 300 mg Single and Double Dose Placebo Single and Double Dose 200 mg Single and Double Dose 300 mg
    Number of subjects
    501
    483
    65
    60
    62
    66
    62
    62
    63
    61
    127
    123
    123
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    253
    243
    40
    30
    27
    32
    32
    24
    37
    31
    72
    67
    58
        From 65-84 years
    245
    237
    24
    30
    35
    34
    29
    38
    26
    29
    53
    56
    64
        85 years and over
    3
    3
    1
    0
    0
    0
    1
    0
    0
    1
    2
    0
    1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.3 ± 10.97
    63.4 ± 11.01
    62 ± 11.4
    63.9 ± 10.8
    64.1 ± 12.8
    62.1 ± 12.4
    62.8 ± 10.3
    65.2 ± 9.4
    62.3 ± 10.8
    64.1 ± 9.4
    62.4 ± 10.8
    63.1 ± 10.8
    64.1 ± 11.2
    Gender categorical
    Units: Subjects
        Female
    175
    170
    23
    21
    20
    19
    29
    23
    24
    16
    52
    45
    36
        Male
    326
    313
    42
    39
    42
    47
    33
    39
    39
    45
    75
    78
    87
    Race
    Units: Subjects
        American Indian or Alaska Native
    6
    5
    1
    0
    1
    1
    0
    2
    0
    1
    1
    0
    2
        Asian
    9
    8
    0
    2
    2
    2
    1
    1
    0
    1
    1
    2
    3
        Black or African
    18
    16
    4
    4
    2
    0
    3
    2
    2
    1
    7
    6
    3
        Native Hawaiian or Other Pacific Islander
    1
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
        White
    465
    451
    59
    53
    56
    63
    58
    57
    61
    58
    117
    114
    114
        Undisclosed
    2
    2
    1
    1
    0
    0
    0
    0
    0
    1
    1
    0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    29
    29
    7
    4
    3
    1
    2
    2
    6
    4
    9
    10
    7
        Not Hispanic or Latino
    472
    454
    58
    56
    59
    65
    60
    60
    57
    57
    118
    113
    116

    End points

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    End points reporting groups
    Reporting group title
    Single Dose
    Reporting group description
    Participants received 1 of 3 different doses (200 milligrams [mg], 300 mg, or 500 mg) of inclisiran or matching placebo on Day 1. These 4 groups received no further study drug or placebo.

    Reporting group title
    Double Dose
    Reporting group description
    Participants received 1 of 3 different doses (100 mg, 200 mg, or 300 mg) of inclisiran or matching placebo on Day 1. These 4 groups then received a second dose on Day 90.

    Subject analysis set title
    Intent-to-Treat (ITT) Population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All participants randomized into the trial. Treatment classification was based on the randomized treatment. This population was used to assess the randomness of treatment allocation.

    Subject analysis set title
    Modified Intent-to-Treat (mITT) Population
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    All randomized participants who received at least 1 dose of study drug and had both the baseline and the 180-day follow-up LDL-C assessment. Treatment classification was based on the randomized treatment. This was the primary population for analysis of the primary and secondary endpoints.

    Subject analysis set title
    Single Dose Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received an SC injection of placebo (0.9% saline) in amounts matched to the doses administered in the Single Dose Arm.

    Subject analysis set title
    Single Dose 200 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants in this group received a 200-mg SC injection of inclisiran on Day 1 of the study.

    Subject analysis set title
    Single Dose 300 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants in this group received a 300-mg SC injection of inclisiran on Day 1 of the study.

    Subject analysis set title
    Single Dose 500 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    On Day 1 of the study, participants in this group received a 500-mg dose of inclisiran as 2 injections, 1 of 300 mg and 1 of 200 mg.

    Subject analysis set title
    Double Dose Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received SC injections of placebo (0.9% saline) in amounts matched to the doses administered in the Double Dose Arm.

    Subject analysis set title
    Double Dose 100 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants in this group received their first 100-mg SC injection of inclisiran on Day 1 of the study. This was followed by a second injection on Day 90.

    Subject analysis set title
    Double Dose 200 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants in this group received their first 200-mg SC injection of inclisiran on Day 1 of the study. This was followed by a second injection on Day 90.

    Subject analysis set title
    Double Dose 300 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants in this group received their first 300-mg SC injection of inclisiran on Day 1 of the study. This was followed by a second injection on Day 90.

    Subject analysis set title
    Single and Double Dose Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis includes all participants in both the single dose and the double dose placebo groups.

    Subject analysis set title
    Single and Double Dose 200 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis includes all participants in both the single dose and the double dose 200 mg groups.

    Subject analysis set title
    Single and Double Dose 300 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis includes all participants in both the single dose and the double dose 300 mg groups.

    Primary: Change From Baseline In LDL-C Levels For Single-Dose Inclisiran At Day 180

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    End point title
    Change From Baseline In LDL-C Levels For Single-Dose Inclisiran At Day 180
    End point description
    This outcome measure evaluated the effect of single-dose (200 mg, 300 mg, 500 mg) inclisiran treatments on LDL-C levels in the mITT population at Day 180. The least square (LS) mean was calculated using a repeated measurement linear effect model. The model included treatment group, baseline value, scheduled visit, and the interaction of treatment group with scheduled visit. The p value was adjusted for multiple comparisons using Dunnett's Test.
    End point type
    Primary
    End point timeframe
    Baseline, Day 180
    End point values
    Single Dose Placebo Single Dose 200 mg Single Dose 300 mg Single Dose 500 mg
    Number of subjects analysed
    64
    60
    60
    60
    Units: percent change
        least squares mean (confidence interval 95%)
    2.1 (-2.9 to 7.2)
    -27.9 (-33.1 to -22.7)
    -38.4 (-43.6 to -33.2)
    -41.9 (-47.2 to -36.7)
    Statistical analysis title
    Placebo versus 200 mg
    Statistical analysis description
    Two-sample t-tests were performed to test the superiority of any dosing group over placebo.
    Comparison groups
    Single Dose Placebo v Single Dose 200 mg
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Dunnett's Test
    Parameter type
    Treatment Difference
    Confidence interval
    Notes
    [1] - The p value was adjusted for multiple comparisons using Dunnett's Test.
    Statistical analysis title
    Placebo versus 300 mg
    Statistical analysis description
    Two-sample t-tests were performed to test the superiority of any dosing group over placebo.
    Comparison groups
    Single Dose Placebo v Single Dose 300 mg
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Dunnett's Test
    Parameter type
    Treatment Difference
    Confidence interval
    Notes
    [2] - The p value was adjusted for multiple comparisons using Dunnett's Test.
    Statistical analysis title
    Placebo versus 500 mg
    Statistical analysis description
    Two-sample t-tests were performed to test the superiority of any dosing group over placebo.
    Comparison groups
    Single Dose Placebo v Single Dose 500 mg
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Dunnett's Test
    Parameter type
    Treatment Difference
    Confidence interval
    Notes
    [3] - The p value was adjusted for multiple comparisons using Dunnett's Test.

    Primary: Change From Baseline In LDL-C Levels For Double-Dose Inclisiran At Day 180

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    End point title
    Change From Baseline In LDL-C Levels For Double-Dose Inclisiran At Day 180
    End point description
    This outcome measure evaluated the effect of double-dose (100 mg, 200 mg, 300 mg) inclisiran treatments on LDL-C levels in the mITT population at Day 180. The LS mean was calculated using a repeated measurement linear effect model. The model included treatment group, baseline value, scheduled visit, and the interaction of treatment group with scheduled visit. The p value was adjusted for multiple comparisons using Dunnett's Test.
    End point type
    Primary
    End point timeframe
    Baseline, Day 180
    End point values
    Double Dose Placebo Double Dose 100 mg Double Dose 200 mg Double Dose 300 mg
    Number of subjects analysed
    61
    59
    60
    59
    Units: percent change
        least squares mean (confidence interval 95%)
    1.8 (-2.6 to 6.3)
    -35.5 (-40 to -31)
    -44.9 (-49.3 to -40.4)
    -52.6 (-57.1 to -48.1)
    Statistical analysis title
    Placebo versus 100 mg
    Statistical analysis description
    Two-sample t-tests were performed to test the superiority of any dosing group over placebo.
    Comparison groups
    Double Dose Placebo v Double Dose 100 mg
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    Dunnett's Test
    Parameter type
    Treatment Difference
    Confidence interval
    Notes
    [4] - The p value was adjusted for multiple comparisons using Dunnett's Test.
    Statistical analysis title
    Placebo versus 200 mg
    Statistical analysis description
    Two-sample t-tests were performed to test the superiority of any dosing group over placebo.
    Comparison groups
    Double Dose Placebo v Double Dose 200 mg
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    < 0.0001
    Method
    Dunnett's Test
    Parameter type
    Treatment Difference
    Confidence interval
    Notes
    [5] - The p value was adjusted for multiple comparisons using Dunnett's Test.
    Statistical analysis title
    Placebo versus 300 mg
    Statistical analysis description
    Two-sample t-tests were performed to test the superiority of any dosing group over placebo.
    Comparison groups
    Double Dose Placebo v Double Dose 300 mg
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [6]
    Method
    Dunnett's Test
    Parameter type
    Treatment Difference
    Confidence interval
    Notes
    [6] - The p value was adjusted for multiple comparisons using Dunnett's Test.

    Secondary: Change From Baseline In LDL-C Levels at Day 90

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    End point title
    Change From Baseline In LDL-C Levels at Day 90
    End point description
    This outcome measure evaluated the effects of single- and double-dose inclisiran on LDL-C levels in the mITT population at Day 90. The LS mean was calculated using a repeated measurement linear effect model. The model included treatment group, baseline value, scheduled visit, and the interaction of treatment group with scheduled visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 90
    End point values
    Single Dose 500 mg Double Dose 100 mg Single and Double Dose Placebo Single and Double Dose 200 mg Single and Double Dose 300 mg
    Number of subjects analysed
    60
    59
    125
    120
    118
    Units: participants
        least squares mean (confidence interval 95%)
    -49 (-53.8 to -44.2)
    -34.2 (-39.1 to -29.3)
    -0.8 (-4.2 to 2.5)
    -41.8 (-45.3 to -38.4)
    -45.7 (-49.2 to -42.3)
    No statistical analyses for this end point

    Secondary: Change From Baseline In LDL-C Levels At Day 60, Day 120, and Day 210

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    End point title
    Change From Baseline In LDL-C Levels At Day 60, Day 120, and Day 210
    End point description
    This outcome measure evaluated the effects of both single- and double-dose inclisiran on LDL-C levels in the mITT population from baseline to Day 60, Day 120, and Day 210.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 60, Day 120, and Day 210
    End point values
    Single Dose Placebo Single Dose 200 mg Single Dose 300 mg Single Dose 500 mg Double Dose Placebo Double Dose 100 mg Double Dose 200 mg Double Dose 300 mg
    Number of subjects analysed
    64 [7]
    60 [8]
    60
    60 [9]
    61 [10]
    59 [11]
    60 [12]
    59 [13]
    Units: percentage change
    arithmetic mean (confidence interval 95%)
        Day 60
    -4.27 (-7.84 to -0.7)
    -44.32 (-50.55 to -38.09)
    -50.87 (-55.62 to -46.12)
    -49.58 (-54.12 to -45.04)
    -1.92 (-6.7 to 2.85)
    -35.73 (-40.23 to -31.23)
    -44.28 (-49.1 to -39.47)
    -50.59 (-55.51 to -45.67)
        Day 120
    -0.91 (-5.17 to 3.34)
    -36.94 (-42.8 to -31.08)
    -43.32 (-48.95 to -37.68)
    -46.42 (-50.63 to -42.22)
    0.17 (-3.61 to 3.95)
    -41.37 (-45.94 to -36.8)
    -49.54 (-54.6 to -44.49)
    -54.73 (-59.88 to -49.58)
        Day 210
    1.45 (-3.61 to 6.06)
    -28.98 (-36.83 to -21.12)
    -35.39 (-41.47 to -29.31)
    -39.2 (-43.71 to -34.68)
    0.58 (-4.58 to 5.74)
    -31.67 (-36.08 to -27.27)
    -42.59 (-47.11 to -38.08)
    -50.54 (-54.83 to -46.25)
    Notes
    [7] - Day 60 (62); Day 210 (62)
    [8] - Day 120 (58)
    [9] - Day 60 (58); Day 120 (57)
    [10] - Day 210 (60)
    [11] - Day 90 (58); Day 120 (58)
    [12] - Day 120 (59)
    [13] - Day 120 (58); Day 210 (58)
    No statistical analyses for this end point

    Secondary: Proportion Of Participants With An LDL-C Greater Than 80% Of The Baseline Value At Day 180 and Day 210

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    End point title
    Proportion Of Participants With An LDL-C Greater Than 80% Of The Baseline Value At Day 180 and Day 210
    End point description
    This outcome measure evaluated the number of participants (single and double dose) in the mITT population with an LDL-C greater than 80% of the baseline value at Day 180 and Day 210.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 180, Day 210
    End point values
    Single Dose Placebo Single Dose 200 mg Single Dose 300 mg Single Dose 500 mg Double Dose Placebo Double Dose 100 mg Double Dose 200 mg Double Dose 300 mg
    Number of subjects analysed
    64 [14]
    60
    60
    60
    61 [15]
    59
    60
    59
    Units: participants
        Day 180
    35
    6
    5
    0
    29
    2
    1
    0
        Day 210
    34
    8
    5
    2
    34
    1
    1
    1
    Notes
    [14] - Day 180 (64); Day 210 (62)
    [15] - Day 180 (61); Day 210 (60)
    No statistical analyses for this end point

    Secondary: Proportion Of Participants With Individual Responsiveness as Measured By LDL-C Levels At Day 90 and Day 180

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    End point title
    Proportion Of Participants With Individual Responsiveness as Measured By LDL-C Levels At Day 90 and Day 180
    End point description
    This outcome measure evaluated the individual responsiveness of participants to inclisiran (single and double dose) in the mITT population as defined by an LDL-C level of <25 mg/deciliter [dL] at Day 90 and Day 180.
    End point type
    Secondary
    End point timeframe
    Day 90, Day 180
    End point values
    Single Dose Placebo Single Dose 200 mg Single Dose 300 mg Single Dose 500 mg Double Dose Placebo Double Dose 100 mg Double Dose 200 mg Double Dose 300 mg
    Number of subjects analysed
    64 [16]
    60
    60 [17]
    60
    61 [18]
    59
    60
    59
    Units: participants
        Day 90
    0
    0
    5
    3
    0
    0
    1
    0
        Day 180
    0
    0
    1
    2
    0
    1
    2
    3
    Notes
    [16] - Day 90 (63)
    [17] - Day 90 (59)
    [18] - Day 90 (60)
    No statistical analyses for this end point

    Secondary: Proportion Of Participants With Greater Or Equal To 50% LDL-C Reduction From Baseline At Day 180

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    End point title
    Proportion Of Participants With Greater Or Equal To 50% LDL-C Reduction From Baseline At Day 180
    End point description
    This outcome measure evaluated the number of participants (single and double dose) in the mITT population with an LDL-C reduction greater than 50% of the baseline value at Day 180.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 180
    End point values
    Single Dose Placebo Single Dose 200 mg Single Dose 300 mg Single Dose 500 mg Double Dose Placebo Double Dose 100 mg Double Dose 200 mg Double Dose 300 mg
    Number of subjects analysed
    64
    60
    60
    60
    61
    59
    60
    59
    Units: participant
    0
    9
    19
    16
    0
    14
    27
    32
    No statistical analyses for this end point

    Secondary: Percentage Change In PCSK9 Levels From Baseline At Day 180

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    End point title
    Percentage Change In PCSK9 Levels From Baseline At Day 180
    End point description
    This outcome measure evaluated the percent change in proprotein convertase subtilisin/kexin type 9 (PCSK9) from baseline to Day 180 in participants (single and double dose) in the mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 180
    End point values
    Single Dose Placebo Single Dose 200 mg Single Dose 300 mg Single Dose 500 mg Double Dose Placebo Double Dose 100 mg Double Dose 200 mg Double Dose 300 mg
    Number of subjects analysed
    64
    60
    60
    60
    61
    59
    60
    59
    Units: percent change
        arithmetic mean (standard deviation)
    2.2 ± 23.4
    -47.9 ± 21
    -56 ± 19.2
    -59.3 ± 18
    -1.2 ± 20.7
    -53.2 ± 20.9
    -66.2 ± 15.6
    -69.1 ± 12.1
    No statistical analyses for this end point

    Secondary: Percentage Change In Other Lipids and Apolipoproteins From Baseline To Day 180

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    End point title
    Percentage Change In Other Lipids and Apolipoproteins From Baseline To Day 180
    End point description
    This outcome measure evaluated the percent change from baseline to Day 180 in cholesterol (total, high-density lipoprotein [HDL], non-HDL) and apolipoproteins (B, A1) in participants (single and double dose) in the mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 180
    End point values
    Single Dose Placebo Single Dose 200 mg Single Dose 300 mg Single Dose 500 mg Double Dose Placebo Double Dose 100 mg Double Dose 200 mg Double Dose 300 mg
    Number of subjects analysed
    64
    60
    60
    60
    61
    59
    60
    59
    Units: percent change
    arithmetic mean (standard deviation)
        Total Cholesterol
    1.8 ± 12.1
    -17.6 ± 19
    -23.7 ± 15.7
    -26.6 ± 10.7
    0.7 ± 12.3
    -22.4 ± 12.4
    -26.8 ± 13
    -33.2 ± 11.3
        Non-HDL Cholesterol
    1.5 ± 16.7
    -25.1 ± 26.2
    -35.2 ± 20.2
    -36.9 ± 14
    1.3 ± 16.9
    -31.7 ± 15.1
    -38.9 ± 16.8
    -46 ± 14.6
        HDL Cholesterol
    3.8 ± 15.6
    4.4 ± 14.8
    8.8 ± 11.1
    6.9 ± 14
    0.5 ± 12.5
    7.6 ± 12.2
    10.3 ± 15.3
    8.6 ± 14.9
        Apolipoprotein B
    1.7 ± 14.7
    -22.9 ± 21
    -30.8 ± 18
    -33.1 ± 12.7
    0.9 ± 13
    -27.8 ± 13.4
    -35 ± 15.8
    -40.9 ± 14.8
        Apolipoprotein A1
    3.6 ± 10.6
    2.9 ± 9.3
    3.8 ± 8.9
    4.1 ± 10.9
    0.8 ± 8.3
    5.5 ± 10.6
    8.6 ± 11.5
    6.2 ± 11.9
    No statistical analyses for this end point

    Secondary: Proportion Of Participants Who Attained Global Lipid Modification Targets For Level Of Atherosclerotic Cardiovascular Disease Risk

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    End point title
    Proportion Of Participants Who Attained Global Lipid Modification Targets For Level Of Atherosclerotic Cardiovascular Disease Risk
    End point description
    This outcome measure evaluated the proportion of participants (single and double dose) in the mITT population who attained a global lipid modification target by baseline cardiovascular risk group, looking specifically at LDL-C levels (mg/dL) in the category of cardiovascular disease (CVD). CVD was defined as a participant who had at least 1 of the following: prior myocardial infarction, prior percutaneous coronary intervention, prior coronary artery bypass graft, prior stroke, prior transient ischemic attack, peripheral artery disease.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 180
    End point values
    Single Dose Placebo Single Dose 200 mg Single Dose 300 mg Single Dose 500 mg Double Dose Placebo Double Dose 100 mg Double Dose 200 mg Double Dose 300 mg
    Number of subjects analysed
    64
    60
    60
    60
    61
    59
    60
    59
    Units: participant
        CVD
    45
    43
    46
    33
    45
    41
    39
    42
        <70 mg/dL
    0
    16
    27
    18
    1
    24
    27
    33
    No statistical analyses for this end point

    Secondary: Percentage Change In Other Lipids And Inflammatory Markers From Baseline To Day 180

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    End point title
    Percentage Change In Other Lipids And Inflammatory Markers From Baseline To Day 180
    End point description
    This outcome measure evaluated the percent change from baseline to Day 180 in triglycerides, very-low-density lipoprotein (VLDL) cholesterol, lipoprotein(a), and high sensitivity C-reactive protein (hsCRP) in participants (single and double dose) in the mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 180
    End point values
    Single Dose Placebo Single Dose 200 mg Single Dose 300 mg Single Dose 500 mg Double Dose Placebo Double Dose 100 mg Double Dose 200 mg Double Dose 300 mg
    Number of subjects analysed
    64
    60
    60
    60
    61
    59
    60
    59
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Triglycerides
    6.4 (-15.9 to 21.9)
    1.1 (-18.5 to 17.8)
    -12.8 (-27.8 to 7.8)
    -12.2 (-25.6 to 7.7)
    -3 (-17.2 to 22.6)
    -6.3 (-17.6 to 10.9)
    0.7 (-22.4 to 11.3)
    -14.2 (-26.4 to 5.4)
        VLDL Cholesterol
    2.4 (-30.7 to 30.5)
    -11.6 (-35.8 to 23.3)
    -23.8 (-43 to -6.4)
    -14.6 (-34.8 to 3.5)
    2.7 (-20 to 26.7)
    -16.4 (-31.3 to 0)
    -21.2 (-38.5 to 13.2)
    -16 (-38.2 to 9.1)
        Lipoprotein(a)
    0.5 (-13.9 to 14.8)
    -14.3 (-29.5 to -3.5)
    -14.3 (-25.4 to -5.6)
    -18.2 (-35 to -1.6)
    0 (-10 to 12.4)
    -14.9 (-26.2 to -1.9)
    -17.3 (-31.9 to -7.7)
    -25.6 (-38.5 to -15.2)
        hsCRP
    -5.3 (-40.8 to 28.4)
    7.1 (-30.7 to 70.9)
    -16.2 (-45.8 to 50)
    -19.8 (-50 to 32.7)
    -20 (-50 to 30)
    -12.5 (-42.9 to 29.4)
    -16.3 (-34.6 to 24.3)
    -16.7 (-50.9 to 33.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 360 days (± 3 days) post randomization and treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo - Single Dose
    Reporting group description
    Participants received an SC injection of placebo (0.9% saline) that matched the doses administered in the Single Dose Arm.

    Reporting group title
    200 mg - Single Dose
    Reporting group description
    Participants in this group only received a 200-mg SC injection of inclisiran on Day 1 of the study.

    Reporting group title
    300 mg - Single Dose
    Reporting group description
    Participants in this group only received a 300-mg SC injection of inclisiran on Day 1 of the study.

    Reporting group title
    500 mg - Single Dose
    Reporting group description
    On Day 1 only of the study, participants in this group received a 500-mg dose of inclisiran as 2 injections, 1 of 300 mg and 1 of 200 mg.

    Reporting group title
    Placebo - Double Dose
    Reporting group description
    Participants received SC injections of placebo (0.9% saline) in amounts that matched doses administered in the Double Dose Arm.

    Reporting group title
    100 mg - Double Dose
    Reporting group description
    Participants in this group received their first 100-mg SC injection of inclisiran on Day 1 of the study. This was followed by a second injection on Day 90.

    Reporting group title
    200 mg - Double Dose
    Reporting group description
    Participants in this group received their first 200-mg SC injection of inclisiran on Day 1 of the study. This was followed by a second injection on Day 90.

    Reporting group title
    300 mg - Double Dose
    Reporting group description
    Participants in this group received their first 300-mg SC injection of inclisiran on Day 1 of the study. This was followed by a second injection on Day 90.

    Serious adverse events
    Placebo - Single Dose 200 mg - Single Dose 300 mg - Single Dose 500 mg - Single Dose Placebo - Double Dose 100 mg - Double Dose 200 mg - Double Dose 300 mg - Double Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 65 (4.62%)
    11 / 60 (18.33%)
    11 / 61 (18.03%)
    8 / 65 (12.31%)
    7 / 62 (11.29%)
    13 / 61 (21.31%)
    8 / 62 (12.90%)
    9 / 61 (14.75%)
         number of deaths (all causes)
    0
    0
    0
    1
    0
    0
    1
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 60 (3.33%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tongue neoplasm malignant stage
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal adenocarcinoma
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma stage 0
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer stage I
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device dislocation
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stent-graft endoleak
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular stent restenosis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    2 / 62 (3.23%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weaning failure
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb crushing injury
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Transaminases increased
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
    1 / 65 (1.54%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    2 / 62 (3.23%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    2 / 65 (3.08%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lacunar stroke
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord ischaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctitis ulcerative
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aorto-oesophageal fistula
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic haemorrhage
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress urinary incontinence
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle necrosis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Listeria sepsis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound abscess
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo - Single Dose 200 mg - Single Dose 300 mg - Single Dose 500 mg - Single Dose Placebo - Double Dose 100 mg - Double Dose 200 mg - Double Dose 300 mg - Double Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 65 (76.92%)
    49 / 60 (81.67%)
    49 / 61 (80.33%)
    54 / 65 (83.08%)
    51 / 62 (82.26%)
    47 / 61 (77.05%)
    49 / 62 (79.03%)
    51 / 61 (83.61%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    1 / 65 (1.54%)
    1 / 62 (1.61%)
    4 / 61 (6.56%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    1
    1
    1
    4
    1
    0
    Contusion
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 60 (1.67%)
    2 / 61 (3.28%)
    2 / 65 (3.08%)
    5 / 62 (8.06%)
    3 / 61 (4.92%)
    1 / 62 (1.61%)
    2 / 61 (3.28%)
         occurrences all number
    1
    1
    2
    3
    5
    4
    1
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 60 (3.33%)
    3 / 61 (4.92%)
    1 / 65 (1.54%)
    3 / 62 (4.84%)
    4 / 61 (6.56%)
    2 / 62 (3.23%)
    1 / 61 (1.64%)
         occurrences all number
    0
    2
    3
    1
    5
    4
    3
    1
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 65 (4.62%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    5 / 62 (8.06%)
    0 / 61 (0.00%)
    3 / 62 (4.84%)
    0 / 61 (0.00%)
         occurrences all number
    3
    1
    1
    0
    6
    0
    3
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 60 (3.33%)
    4 / 61 (6.56%)
    1 / 65 (1.54%)
    2 / 62 (3.23%)
    0 / 61 (0.00%)
    2 / 62 (3.23%)
    0 / 61 (0.00%)
         occurrences all number
    1
    2
    5
    1
    2
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 65 (3.08%)
    4 / 60 (6.67%)
    7 / 61 (11.48%)
    3 / 65 (4.62%)
    3 / 62 (4.84%)
    1 / 61 (1.64%)
    6 / 62 (9.68%)
    3 / 61 (4.92%)
         occurrences all number
    2
    4
    7
    3
    3
    1
    6
    3
    Epistaxis
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences all number
    4
    0
    0
    1
    1
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 65 (4.62%)
    1 / 60 (1.67%)
    2 / 61 (3.28%)
    2 / 65 (3.08%)
    6 / 62 (9.68%)
    3 / 61 (4.92%)
    3 / 62 (4.84%)
    3 / 61 (4.92%)
         occurrences all number
    4
    1
    2
    2
    8
    3
    3
    3
    Headache
         subjects affected / exposed
    6 / 65 (9.23%)
    2 / 60 (3.33%)
    2 / 61 (3.28%)
    2 / 65 (3.08%)
    5 / 62 (8.06%)
    5 / 61 (8.20%)
    1 / 62 (1.61%)
    5 / 61 (8.20%)
         occurrences all number
    6
    2
    2
    2
    7
    6
    1
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 65 (7.69%)
    2 / 60 (3.33%)
    4 / 61 (6.56%)
    2 / 65 (3.08%)
    6 / 62 (9.68%)
    2 / 61 (3.28%)
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    7
    2
    4
    2
    7
    2
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 65 (1.54%)
    4 / 60 (6.67%)
    2 / 61 (3.28%)
    1 / 65 (1.54%)
    2 / 62 (3.23%)
    0 / 61 (0.00%)
    2 / 62 (3.23%)
    1 / 61 (1.64%)
         occurrences all number
    1
    5
    2
    1
    2
    0
    2
    1
    Diarrhoea
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 60 (1.67%)
    4 / 61 (6.56%)
    4 / 65 (6.15%)
    2 / 62 (3.23%)
    3 / 61 (4.92%)
    7 / 62 (11.29%)
    5 / 61 (8.20%)
         occurrences all number
    1
    1
    4
    5
    2
    3
    7
    6
    Abdominal pain
         subjects affected / exposed
    2 / 65 (3.08%)
    3 / 60 (5.00%)
    2 / 61 (3.28%)
    0 / 65 (0.00%)
    3 / 62 (4.84%)
    2 / 61 (3.28%)
    1 / 62 (1.61%)
    4 / 61 (6.56%)
         occurrences all number
    2
    4
    2
    0
    3
    2
    1
    5
    Nausea
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
    4 / 65 (6.15%)
    3 / 62 (4.84%)
    2 / 61 (3.28%)
    4 / 62 (6.45%)
    3 / 61 (4.92%)
         occurrences all number
    2
    1
    1
    4
    3
    2
    4
    3
    Vomiting
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 60 (1.67%)
    2 / 61 (3.28%)
    1 / 65 (1.54%)
    0 / 62 (0.00%)
    0 / 61 (0.00%)
    4 / 62 (6.45%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    2
    1
    0
    0
    4
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 65 (3.08%)
    4 / 60 (6.67%)
    4 / 61 (6.56%)
    4 / 65 (6.15%)
    1 / 62 (1.61%)
    2 / 61 (3.28%)
    5 / 62 (8.06%)
    3 / 61 (4.92%)
         occurrences all number
    2
    6
    4
    4
    1
    2
    5
    3
    Back pain
         subjects affected / exposed
    5 / 65 (7.69%)
    4 / 60 (6.67%)
    4 / 61 (6.56%)
    4 / 65 (6.15%)
    2 / 62 (3.23%)
    6 / 61 (9.84%)
    1 / 62 (1.61%)
    4 / 61 (6.56%)
         occurrences all number
    5
    4
    4
    4
    2
    6
    1
    5
    Myalgia
         subjects affected / exposed
    3 / 65 (4.62%)
    2 / 60 (3.33%)
    6 / 61 (9.84%)
    3 / 65 (4.62%)
    3 / 62 (4.84%)
    7 / 61 (11.48%)
    5 / 62 (8.06%)
    5 / 61 (8.20%)
         occurrences all number
    4
    2
    7
    3
    3
    7
    5
    8
    Musculoskeletal pain
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 60 (3.33%)
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    4 / 62 (6.45%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    6 / 61 (9.84%)
         occurrences all number
    1
    2
    0
    1
    5
    0
    0
    6
    Pain in extremity
         subjects affected / exposed
    2 / 65 (3.08%)
    2 / 60 (3.33%)
    1 / 61 (1.64%)
    2 / 65 (3.08%)
    4 / 62 (6.45%)
    1 / 61 (1.64%)
    4 / 62 (6.45%)
    1 / 61 (1.64%)
         occurrences all number
    2
    2
    1
    2
    4
    2
    5
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 65 (0.00%)
    3 / 60 (5.00%)
    2 / 61 (3.28%)
    1 / 65 (1.54%)
    2 / 62 (3.23%)
    3 / 61 (4.92%)
    1 / 62 (1.61%)
    1 / 61 (1.64%)
         occurrences all number
    0
    4
    2
    1
    2
    3
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    4 / 65 (6.15%)
    8 / 60 (13.33%)
    9 / 61 (14.75%)
    9 / 65 (13.85%)
    8 / 62 (12.90%)
    8 / 61 (13.11%)
    5 / 62 (8.06%)
    11 / 61 (18.03%)
         occurrences all number
    4
    13
    12
    10
    9
    13
    5
    12
    Urinary tract infection
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 60 (1.67%)
    5 / 61 (8.20%)
    0 / 65 (0.00%)
    4 / 62 (6.45%)
    1 / 61 (1.64%)
    1 / 62 (1.61%)
    2 / 61 (3.28%)
         occurrences all number
    1
    1
    10
    0
    4
    1
    2
    2
    Influenza
         subjects affected / exposed
    3 / 65 (4.62%)
    3 / 60 (5.00%)
    4 / 61 (6.56%)
    5 / 65 (7.69%)
    2 / 62 (3.23%)
    3 / 61 (4.92%)
    4 / 62 (6.45%)
    5 / 61 (8.20%)
         occurrences all number
    3
    3
    4
    5
    2
    4
    4
    5
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 65 (3.08%)
    2 / 60 (3.33%)
    4 / 61 (6.56%)
    5 / 65 (7.69%)
    2 / 62 (3.23%)
    2 / 61 (3.28%)
    1 / 62 (1.61%)
    3 / 61 (4.92%)
         occurrences all number
    2
    2
    5
    6
    2
    3
    1
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2016
    • Addition of an interim analysis of lipids and PCSK9 at Day 90. Addition of a secondary endpoint for LDL-C levels at Day 90 • The exploratory objective has been re-worded to provide a more specific description of the event terms that will be reported • Any participants in whom LDL-C levels have not returned to >80% of baseline values will continue to be followed-up monthly as part of this study until either this level has been reached or until Day 360. Additional follow-up visits added to schedule • Anti-drug antibodies will be assessed when LDL-C returns to >80% baseline or at Day 360 • Amended exclusion criterion 11 to state that contraception must be used during the entire study period • Additional exclusion criterion 17 to exclude participants that have received monoclonal antibodies directed towards PCSK9 • Additional description of sample size calculation and statistical methods • Removal of description of the open-label extension study • Neurological examination added as part of the physical examination • Addition of monthly pregnancy test for women of childbearing potential • Addition of Sampson Criteria for diagnosing anaphylaxis
    18 Mar 2016
    • Additional anti-drug antibody assessments at Day 60 and Day 90 (and at Day 150 and Day 180 in participants that received a second dose). • Addition of reference to the open-label extension study • Additional information on completed in vitro and in vivo non-clinical studies • Specify that height and weight to be recorded as part of the physical examination
    12 Apr 2016
    • Amended exclusion criterion 13 to exclude participants with a history of alcohol / drug abuse within the last five years • Amended exclusion criteria 17 to clarify that participants should not have received monoclonal antibodies directed towards PCSK9 within 90 days of screening • Specified that abnormal neurological examination or anaphylactic reaction must be recorded on the source documentation and the electronic case report form

    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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