Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43871   clinical trials with a EudraCT protocol, of which   7290   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Multicenter, Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of AMG 145 on LDL-C in Subjects With Severe Familial Hypercholesterolemia

    Summary
    EudraCT number
    		 2011-005400-15
    Trial protocol
    		 BE   GR   CZ   GB   ES   IT   NL  
    Global end of trial date
    11 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Nov 2018
    First version publication date
    22 Nov 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20110271
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01624142
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to characterize the safety and tolerability of long-term administration of evolocumab (AMG 145) among subjects with severe familial hypercholesterolemia.
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP), and Food and Drug Administration (FDA) regulations/guidelines. The Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs) for this study reviewed the study protocol, amendments, and the informed consent form (ICF). No subjects were recruited into the study and no investigational product was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals. The investigator or his/her designee informed the subject of all aspects pertaining to the subject’s participation in the study before any screening procedures were performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 37
    Country: Number of subjects enrolled
    United States: 32
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Czech Republic: 28
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Israel: 5
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Lebanon: 1
    Country: Number of subjects enrolled
    Netherlands: 23
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Brazil: 25
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Japan: 9
    Country: Number of subjects enrolled
    New Zealand: 11
    Country: Number of subjects enrolled
    South Africa: 31
    Worldwide total number of subjects
    300
    EEA total number of subjects
    138
    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)
    14
    Adults (18-64 years)
    240
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were enrolled at 43 centers in Canada, South Africa, Czech Republic, Netherlands, USA, France, Spain, Italy, Belgium, Australia, New Zealand, United Kingdom, Japan, Israel, Greece, Lebanon, Brazil, and Hong Kong between 01 June 2012 and 19 March 2015.

    Pre-assignment
    Screening details
    		 A total of 246 participants enrolled directly in Study 20110271 and 54 participants rolled over from Study 20110233 (NCT01588496). Results are reported separately for participants with homozygous familial hypercholesterolemia (HoFH) and non-HoFH severe familial hypercholesterolemia (FH) (ie, all those not meeting the protocol criteria for HoFH).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HoFH
    Arm description
    		 Participants with homozygous familial hypercholesterolemia (HoFH) received 420 mg evolocumab every month (participants not on lipid apheresis) or every 2 weeks (participants on lipid apheresis) for up to 5 years. Participants could switch dosing regimens at week 12 or 24 based on LDL-C and serum unbound proprotein convertase subtilisin/kexin type 9 (PCSK9) levels.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evolocumab
    Investigational medicinal product code
    AMG 145
    Other name
    Repatha
    Pharmaceutical forms
    Solution for injection, Solution for injection in pre-filled pen, Solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Evolocumab 420 mg via subcutaneous injection, initially administered either once a month (QM) (non-apheresis subjects) or once every 2 weeks (Q2W) (apheresis subjects).

    Arm title
    		 Severe FH
    Arm description
    		 Participants with severe (non-HoFH) familial hypercholesterolemia (FH) received 420 mg evolocumab every month (participants not on lipid apheresis) or every 2 weeks (participants on lipid apheresis) for up to 5 years. Participants could switch dosing regimens at week 12 or 24 based on LDL-C and serum unbound PCSK9 levels.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evolocumab
    Investigational medicinal product code
    AMG 145
    Other name
    Repatha
    Pharmaceutical forms
    Solution for injection, Solution for injection in pre-filled pen, Solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Evolocumab 420 mg via subcutaneous injection, initially administered either once a month (QM) (non-apheresis subjects) or once every 2 weeks (Q2W) (apheresis subjects).

    Number of subjects in period 1
    		HoFH Severe FH
    Started
    106
    194
    Completed
    74
    178
    Not completed
    32
    16
         Adverse event, serious fatal
    3
    6
         Consent withdrawn by subject
    14
    4
         Study Closure
    12
    6
         Other
    1
    -
         Lost to follow-up
    2
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    HoFH
    Reporting group description
    		 Participants with homozygous familial hypercholesterolemia (HoFH) received 420 mg evolocumab every month (participants not on lipid apheresis) or every 2 weeks (participants on lipid apheresis) for up to 5 years. Participants could switch dosing regimens at week 12 or 24 based on LDL-C and serum unbound proprotein convertase subtilisin/kexin type 9 (PCSK9) levels.

    Reporting group title
    Severe FH
    Reporting group description
    		 Participants with severe (non-HoFH) familial hypercholesterolemia (FH) received 420 mg evolocumab every month (participants not on lipid apheresis) or every 2 weeks (participants on lipid apheresis) for up to 5 years. Participants could switch dosing regimens at week 12 or 24 based on LDL-C and serum unbound PCSK9 levels.

    Reporting group values
    		 HoFH Severe FH Total
    Number of subjects
    		 106 194 300
    Age Categorical
    Baseline characteristics for parent study rollover subjects are defined at the parent study baseline.
    Units: Subjects
        <=18 years
    		 14 0 14
        Between 18 and 65 years
    		 88 152 240
        >=65 years
    		 4 42 46
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.3 ( 14.4 ) 54.7 ( 11.9 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 54 78 132
        Male
    		 52 116 168
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 13 3 16
        Black or African American
    		 0 6 6
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        White
    		 85 179 264
        Other
    		 7 4 11
        Mixed Race
    		 0 2 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 5 22 27
        Not Hispanic or Latino
    		 101 172 273
        Unknown or Not Reported
    		 0 0 0
    Low-density Lipoprotein Cholesterol (LDL-C) Concentration
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 329.0 ( 136.7 ) 192.7 ( 64.6 ) -
    Non-high-density Lipoprotein Cholesterol (non-HDL-C) Concentration
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 350.5 ( 138.4 ) 222.1 ( 68.3 ) -
    Lipoprotein (a) Concentration
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 104.7 ( 100.6 ) 127.1 ( 142.8 ) -
    Apolipoprotein B Concentration
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 200.7 ( 69.9 ) 139.2 ( 35.6 ) -
    Total Cholesterol/HDL-C Ratio
    Units: ratio
        arithmetic mean (standard deviation)
    		 11.473 ( 6.312 ) 6.055 ( 2.397 ) -
    Apolipoprotein B/Apoliprotein A1 Ratio
    Units: ratio
        arithmetic mean (standard deviation)
    		 1.984 ( 0.950 ) 1.023 ( 0.355 ) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    HoFH
    Reporting group description
    		 Participants with homozygous familial hypercholesterolemia (HoFH) received 420 mg evolocumab every month (participants not on lipid apheresis) or every 2 weeks (participants on lipid apheresis) for up to 5 years. Participants could switch dosing regimens at week 12 or 24 based on LDL-C and serum unbound proprotein convertase subtilisin/kexin type 9 (PCSK9) levels.

    Reporting group title
    Severe FH
    Reporting group description
    		 Participants with severe (non-HoFH) familial hypercholesterolemia (FH) received 420 mg evolocumab every month (participants not on lipid apheresis) or every 2 weeks (participants on lipid apheresis) for up to 5 years. Participants could switch dosing regimens at week 12 or 24 based on LDL-C and serum unbound PCSK9 levels.

    Primary: Number of Participants with Adverse Events

    		 Close Top of page
    End point title
    		 Number of Participants with Adverse Events [1]
    End point description
    The severity of each adverse event (AE) was graded according to the National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) grading scale, where grade 1 = mild AE, grade 2 = moderate AE, grade 3 = severe AE, grade 4 = life-threatening AE and grade 5 = death due to AE.
    End point type
    Primary
    End point timeframe
    From first dose of study drug in Study 20110271 up to 30 days after the last dose or until the end of study date, whichever was earlier; median duration of treatment was 48.7 months.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing was conducted. The primary clinical hypothesis was that long-term exposure of evolocumab would be safe and well tolerated in subjects with severe familial hypercholesterolemia.
    End point values
    		 HoFH Severe FH
    Number of subjects analysed
    106
    194
    Units: participants
        All adverse events (AEs)
    94
    174
        Adverse events ≥ grade 2
    76
    143
        Adverse events ≥ grade 3
    38
    68
        Adverse events ≥ grade 4
    4
    14
        Serious adverse events (SAEs)
    29
    57
        AEs Leading to discontinuation of evolocumab
    3
    8
        Fatal adverse events
    2
    5
        Device-related adverse events
    6
    18
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Low-density Lipoprotein Cholesterol (LDL-C)

    		 Close Top of page
    End point title
    		 Percent Change from Baseline in Low-density Lipoprotein Cholesterol (LDL-C)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216
    End point values
    		 HoFH Severe FH
    Number of subjects analysed
    106
    194
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Week 4 (n = 87, 183)
    -20.42 (-38.25 to -8.28)
    -54.95 (-66.67 to -44.55)
        Week 6 (n = 83, 166)
    -18.32 (-36.09 to -4.16)
    -67.57 (-79.54 to -53.93)
        Week 8 (n = 94, 187)
    -20.28 (-37.81 to -8.44)
    -55.03 (-68.58 to -42.07)
        Week 12 (n = 104, 191)
    -18.26 (-36.06 to -7.76)
    -57.11 (-68.00 to -42.80)
        Week 16 (n = 102, 188)
    -23.15 (-39.23 to -7.87)
    -57.53 (-67.99 to -44.95)
        Week 20 (n = 101, 185)
    -25.37 (-45.99 to -8.96)
    -57.26 (-67.48 to -44.68)
        Week 24 (n = 99, 191)
    -21.84 (-41.39 to -8.11)
    -57.10 (-67.05 to -43.70)
        Week 36 (n = 94, 187)
    -26.79 (-46.44 to -8.28)
    -56.08 (-68.70 to -44.47)
        Week 48 (n = 93, 197)
    -25.50 (-44.79 to -4.43)
    -59.67 (-69.14 to -47.88)
        Week 60 (n = 88, 186)
    -27.26 (-44.58 to -4.28)
    -57.13 (-68.42 to -42.65)
        Week 72 (n = 85, 184)
    -27.11 (-51.06 to -12.03)
    -55.73 (-70.52 to -42.76)
        Week 84 (n = 82, 180)
    -27.96 (-50.29 to -7.96)
    -56.02 (-68.49 to -42.18)
        Week 96 (n = 82, 180)
    -22.47 (-46.53 to -8.12)
    -57.10 (-69.53 to -41.66)
        Week 108 (n = 82, 181)
    -26.15 (-44.58 to -5.62)
    -60.57 (-69.47 to -43.15)
        Week 120 (n = 82, 184)
    -26.66 (-43.43 to -7.42)
    -56.76 (-69.48 to -41.70)
        Week 132 (n = 81, 177)
    -28.25 (-48.23 to -9.42)
    -55.25 (-68.17 to -39.89)
        Week 144 (n = 79, 180)
    -28.33 (-49.27 to -10.33)
    -56.48 (-69.26 to -40.69)
        Week 156 (n = 80, 181)
    -23.65 (-47.66 to -11.05)
    -55.38 (-69.48 to -41.03)
        Week 168 (n = 76, 171)
    -29.52 (-51.35 to -4.41)
    -54.77 (-67.16 to -36.42)
        Week 180 (n = 74, 166)
    -25.66 (-53.71 to -9.87)
    -54.08 (-71.53 to -37.55)
        Week 192 (n = 74, 147)
    -30.12 (-53.23 to -11.81)
    -52.19 (-66.79 to -33.99)
        Week 204 (n = 75, 129)
    -29.62 (-47.43 to -6.11)
    -59.59 (-70.50 to -39.06)
        Week 216 (n = 68, 96)
    -32.22 (-46.65 to -8.97)
    -50.62 (-67.73 to -32.31)
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Non-high-density Lipoprotein Cholesterol (non-HDL-C)

    		 Close Top of page
    End point title
    		 Percent Change from Baseline in Non-high-density Lipoprotein Cholesterol (non-HDL-C)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216
    End point values
    		 HoFH Severe FH
    Number of subjects analysed
    106
    194
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Week 4 (n = 88, 183)
    -19.62 (-35.54 to -7.84)
    -50.00 (-59.92 to -39.88)
        Week 6 (n = 85 168)
    -18.17 (-33.88 to -4.29)
    -59.76 (-70.50 to -49.23)
        Week 8 (n = 94, 188)
    -20.29 (-35.94 to -9.28)
    -50.61 (-58.49 to -37.91)
        Week 12 (n = 105, 192)
    -17.05 (-32.03 to -6.99)
    -50.25 (-61.49 to -38.63)
        Week 16 (n = 102, 188)
    -21.73 (-37.81 to -7.88)
    -51.31 (-59.76 to -40.40)
        Week 20 (n = 101, 188)
    -24.09 (-43.06 to -7.76)
    -50.76 (-59.44 to -38.67)
        Week 24 (n = 100, 192)
    -21.88 (-38.81 to -9.54)
    -51.12 (-60.67 to -38.52)
        Week 36 (n = 95, 190)
    -22.43 (-44.08 to -6.22)
    -49.65 (-61.00 to -38.26)
        Week 48 (n = 94, 190)
    -24.08 (-43.47 to -3.98)
    -51.12 (-61.58 to -42.11)
        Week 60 (n = 89, 189)
    -24.81 (-42.96 to -2.67)
    -49.73 (-61.61 to -38.00)
        Week 72 (n = 85, 188)
    -25.88 (-48.21 to -9.47)
    -48.94 (-61.14 to -36.08)
        Week 84 (n = 83, 184)
    -21.00 (-42.68 to -7.45)
    -49.50 (-62.07 to -35.14)
        Week 96 (n = 83, 184)
    -21.10 (-42.84 to -7.85)
    -49.53 (-63.80 to -36.86)
        Week 108 (n = 83, 186)
    -24.17 (-43.01 to -5.69)
    -52.86 (-61.20 to -38.11)
        Week 120 (n = 82, 185)
    -23.21 (-40.37 to -6.23)
    -49.45 (-60.48 to -35.91)
        Week 132 (n = 82, 182)
    -26.39 (-40.28 to -7.19)
    -49.49 (-60.95 to -33.66)
        Week 144 (n = 81, 183)
    -25.38 (-45.55 to -8.08)
    -49.81 (-61.69 to -33.88)
        Week 156 (n = 80, 184)
    -22.35 (-45.47 to -10.50)
    -50.15 (-60.81 to -36.11)
        Week 168 (n = 76, 176)
    -27.97 (-48.82 to -4.36)
    -47.93 (-60.71 to -31.01)
        Week 180 (n = 74, 167)
    -26.32 (-49.82 to -8.62)
    -48.43 (-62.22 to -33.06)
        Week 192 (n = 75, 151)
    -27.61 (-49.49 to -9.29)
    -44.50 (-57.71 to -29.77)
        Week 204 (n = 75, 131)
    -27.22 (-45.14 to -5.73)
    -50.84 (-64.12 to -36.03)
        Week 216 (n = 68, 98)
    -31.40 (-42.75 to -9.67)
    -45.30 (-61.45 to -26.32)
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Lipoprotein (a)

    		 Close Top of page
    End point title
    		 Percent Change from Baseline in Lipoprotein (a)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216
    End point values
    		 HoFH Severe FH
    Number of subjects analysed
    106
    194
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Week 4 (n = 87, 183)
    -11.11 (-27.50 to 0.0)
    -20.49 (-39.84 to -11.61)
        Week 6 (n = 85, 169)
    -8.97 (-24.21 to 3.76)
    -24.42 (-45.95 to -9.38)
        Week 8 (n = 94, 188)
    -9.95 (-25.00 to 3.23)
    -21.51 (-39.84 to -9.09)
        Week 12 (n = 105, 192)
    -7.69 (-21.64 to 6.83)
    -24.40 (-40.28 to -9.09)
        Week 16 (n = 103, 188)
    -8.93 (-25.00 to 4.76)
    -23.08 (-38.88 to -7.62)
        Week 20 (n = 100, 188)
    -13.52 (-29.36 to 0.00)
    -22.21 (-39.34 to -5.98)
        Week 24 (n = 100, 192)
    -10.46 (-23.75 to 1.00)
    -25.99 (-41.81 to -9.09)
        Week 36 (n = 95, 190)
    -15.14 (-28.18 to 0.00)
    -24.26 (-41.30 to -7.85)
        Week 48 (n = 94, 189)
    -13.17 (-30.51 to 0.00)
    -26.32 (-41.94 to -10.49)
        Week 60 (n = 90, 189)
    -13.04 (-35.00 to 2.86)
    -24.05 (-41.97 to -7.63)
        Week 72 (n = 86, 188)
    -17.43 (-37.19 to 5.88)
    -24.23 (-43.96 to -6.81)
        Week 84 (n = 84, 184)
    -14.12 (-36.73 to 0.63)
    -24.12 (-44.05 to -8.02)
        Week 96 (n = 83, 184)
    -17.24 (-33.33 to 0.49)
    -31.28 (-47.33 to -13.34)
        Week 108 (n = 83, 186)
    -21.43 (-42.50 to 0.00)
    -32.44 (-48.65 to -12.69)
        Week 120 (n = 82, 186)
    -20.16 (-33.25 to 0.00)
    -31.22 (-45.00 to -11.40)
        Week 132 (n = 82, 182)
    -19.15 (-37.68 to 0.00)
    -29.32 (-49.82 to -12.29)
        Week 144 (n = 81, 183)
    -23.64 (-47.06 to 0.00)
    -30.36 (-48.17 to -11.92)
        Week 156 (n = 80, 184)
    -18.40 (-42.14 to -2.33)
    -28.10 (-47.35 to -9.09)
        Week 168 (n = 76, 176)
    -22.94 (-41.01 to -0.49)
    -23.96 (-45.64 to -9.09)
        Week 180 (n = 74, 168)
    -17.29 (-43.83 to 0.00)
    -26.23 (-46.01 to -8.83)
        Week 192 (n = 75, 151)
    -22.78 (-44.44 to 0.00)
    -20.00 (-37.75 to -2.44)
        Week 204 (n = 75, 131)
    -16.33 (-38.46 to 3.95)
    -14.29 (-34.38 to 10.00)
        Week 216 (n = 68, 98)
    -14.06 (-36.07 to 4.08)
    -0.67 (-23.64 to 23.81)
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Apolipoprotein B

    		 Close Top of page
    End point title
    		 Percent Change from Baseline in Apolipoprotein B
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216
    End point values
    		 HoFH Severe FH
    Number of subjects analysed
    106
    194
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Week 4 (n = 88, 183)
    -16.91 (-31.67 to -6.81)
    -43.84 (-54.59 to -34.40)
        Week 6 (n = 85, 169)
    -16.25 (-27.82 to -1.96)
    -56.70 (-67.23 to -46.11)
        Week 8 (n = 94, 188)
    -17.57 (-32.00 to -6.24)
    -43.95 (-55.69 to -31.55)
        Week 12 (n = 105, 192)
    -13.11 (-26.87 to -3.49)
    -45.78 (-55.16 to -32.65)
        Week 16 (n = 102, 188)
    -18.65 (-34.77 to -8.35)
    -45.72 (-55.23 to -35.39)
        Week 20 (n = 101, 188)
    -22.60 (-39.05 to -5.03)
    -45.16 (-53.93 to -33.18)
        Week 24 (n = 100, 192)
    -20.09 (-33.04 to -3.97)
    -44.87 (-55.32 to -31.01)
        Week 36 (n = 95, 190)
    -16.48 (-36.43 to -2.56)
    -43.33 (-55.12 to -29.10)
        Week 48 (n = 94, 190)
    -15.90 (-33.60 to -4.15)
    -45.38 (-55.40 to -33.93)
        Week 60 (n = 90, 189)
    -15.99 (-38.12 to -0.27)
    -44.81 (-56.07 to -31.33)
        Week 72 (n = 86, 188)
    -20.70 (-42.02 to -3.17)
    -44.07 (-55.61 to -32.72)
        Week 84 (n = 84, 184)
    -19.52 (-35.66 to -0.09)
    -43.87 (-55.50 to -32.13)
        Week 96 (n = 83, 184)
    -15.07 (-36.34 to -3.67)
    -42.31 (-57.65 to -29.89)
        Week 108 (n = 83, 186)
    -19.45 (-36.07 to 5.03)
    -46.30 (-55.41 to -32.21)
        Week 120 (n = 82, 185)
    -21.58 (-33.33 to -1.57)
    -44.33 (-54.68 to -30.00)
        Week 132 (n = 82, 181)
    -22.44 (-35.70 to -3.75)
    -43.48 (-54.90 to -28.22)
        Week 144 (n = 81, 183)
    -21.24 (-41.89 to -3.55)
    -41.64 (-54.36 to -27.85)
        Week 156 (n = 80, 184)
    -18.30 (-36.66 to -5.63)
    -44.04 (-55.16 to -29.73)
        Week 168 (n = 76, 176)
    -20.38 (-41.58 to -2.81)
    -40.20 (-52.22 to -25.78)
        Week 180 (n = 74, 168)
    -19.51 (-39.73 to -3.02)
    -41.58 (-54.70 to -24.57)
        Week 192 (n = 75, 151)
    -19.38 (-39.63 to -2.63)
    -37.02 (-52.06 to -21.08)
        Week 204 (n = 75, 131)
    -21.64 (-36.15 to -5.48)
    -43.19 (-56.81 to -28.81)
        Week 216 (n = 68, 98)
    -22.68 (-35.34 to -4.51)
    -35.95 (-53.05 to -23.95)
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Total Cholesterol/HDL-C Ratio

    		 Close Top of page
    End point title
    		 Percent Change from Baseline in Total Cholesterol/HDL-C Ratio
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216
    End point values
    		 HoFH Severe FH
    Number of subjects analysed
    106
    194
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Week 4 (n = 88, 183)
    -21.32 (-38.45 to -10.36)
    -43.49 (-53.07 to -33.78)
        Week 6 (n = 85, 168)
    -23.25 (-35.54 to -7.14)
    -52.38 (-60.97 to -42.29)
        Week 8 (n = 94, 188)
    -23.93 (-35.26 to -5.42)
    -43.44 (-51.21 to -34.81)
        Week 12 (n = 105, 192)
    -21.20 (-34.98 to -9.31)
    -44.75 (-53.20 to -35.12)
        Week 16 (n = 102, 188)
    -24.01 (-36.52 to -8.86)
    -45.31 (-52.38 to -34.95)
        Week 20 (n = 101, 188)
    -24.69 (-36.39 to -4.29)
    -43.07 (-51.89 to -33.54)
        Week 24 (n = 100, 192)
    -23.53 (-38.59 to -9.10)
    -43.79 (-52.96 to -34.28)
        Week 36 (n = 95, 190)
    -27.16 (-42.86 to -9.12)
    -42.69 (-53.01 to -30.99)
        Week 48 (n = 94, 190)
    -26.54 (-43.73 to -8.03)
    -44.68 (-54.47 to -33.90)
        Week 60 (n = 89, 189)
    -22.80 (-45.57 to -5.13)
    -43.82 (-54.01 to -32.46)
        Week 72 (n = 85, 188)
    -24.79 (-42.72 to -9.47)
    -42.64 (-54.28 to -30.73)
        Week 84 (n = 83, 184)
    -22.62 (-41.45 to -6.24)
    -43.16 (-53.15 to -27.42)
        Week 96 (n = 83, 184)
    -23.00 (-38.97 to -10.33)
    -42.46 (-54.03 to -31.69)
        Week 108 (n = 83, 186)
    -25.03 (-41.12 to -4.98)
    -43.68 (-53.91 to -32.90)
        Week 120 (n = 82, 185)
    -25.40 (-42.55 to -6.92)
    -42.42 (-54.18 to -30.87)
        Week 132 (n = 82, 182)
    -25.66 (-41.29 to -5.10)
    -42.14 (-53.54 to -30.15)
        Week 144 (n = 81, 183)
    -27.79 (-44.96 to -6.39)
    -43.40 (-54.91 to -28.80)
        Week 156 (n = 80, 184)
    -25.52 (-45.62 to -9.87)
    -43.85 (-53.49 to -29.86)
        Week 168 (n = 76, 176)
    -26.30 (-46.28 to -8.75)
    -41.59 (-52.67 to -24.39)
        Week 180 (n = 74, 167)
    -29.53 (-47.74 to -7.54)
    -40.13 (-54.50 to -28.99)
        Week 192 (n = 75, 151)
    -27.79 (-47.16 to -12.15)
    -38.24 (-53.80 to -25.34)
        Week 204 (n = 75, 131)
    -27.32 (-42.19 to -7.20)
    -43.13 (-57.50 to -31.50)
        Week 216 (n = 68, 98)
    -30.92 (-42.09 to -8.93)
    -40.78 (-52.60 to -26.46)
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio

    		 Close Top of page
    End point title
    		 Percent Change from Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216
    End point values
    		 HoFH Severe FH
    Number of subjects analysed
    106
    194
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Week 4 (n = 88, 183)
    -23.06 (-39.88 to -6.22)
    -46.79 (-57.95 to -37.69)
        Week 6 (n = 85, 169)
    -21.38 (-36.90 to -10.11)
    -59.77 (-68.35 to -48.98)
        Week 8 (n = 94, 188)
    -21.53 (-36.51 to -4.66)
    -47.82 (-57.87 to -37.07)
        Week 12 (n = 105, 192)
    -16.67 (-30.72 to -4.37)
    -48.63 (-59.21 to -38.16)
        Week 16 (n = 102, 188)
    -22.52 (-42.86 to -8.97)
    -48.98 (-58.13 to -39.59)
        Week 20 (n = 101, 188)
    -25.41 (-41.87 to -12.43)
    -49.12 (-57.11 to -38.09)
        Week 24 (n = 100, 192)
    -22.97 (-38.08 to -8.99)
    -49.92 (-58.44 to -37.29)
        Week 36 (n = 95, 190)
    -26.86 (-41.04 to -7.69)
    -49.02 (-58.10 to -35.67)
        Week 48 (n = 94, 190)
    -25.96 (-43.38 to -12.26)
    -49.35 (-59.34 to -38.98)
        Week 60 (n = 90, 189)
    -24.31 (-44.46 to -6.67)
    -48.57 (-59.11 to -35.94)
        Week 72 (n = 86, 188)
    -23.63 (-45.15 to -10.89)
    -48.94 (-60.36 to -38.76)
        Week 84 (n = 84, 184)
    -24.09 (-43.12 to -4.16)
    -49.47 (-59.73 to -34.54)
        Week 96 (n = 83, 184)
    -24.75 (-45.92 to -8.61)
    -48.45 (-60.40 to -36.17)
        Week 108 (n = 83, 186)
    -26.03 (-41.27 to -4.78)
    -50.18 (-60.18 to -37.84)
        Week 120 (n = 82, 185)
    -26.45 (-44.21 to -12.32)
    -49.75 (-59.38 to -36.17)
        Week 132 (n = 82, 181)
    -24.26 (-47.15 to -7.81)
    -48.54 (-58.39 to -32.01)
        Week 144 (n = 81, 183)
    -28.09 (-48.50 to -7.81)
    -47.44 (-59.12 to -33.82)
        Week 156 (n = 80, 184)
    -27.21 (-46.95 to -12.25)
    -49.10 (-59.29 to -35.31)
        Week 168 (n = 76, 176)
    -32.16 (-47.39 to -12.53)
    -44.46 (-56.03 to -30.06)
        Week 180 (n = 74, 168)
    -28.70 (-48.45 to -9.71)
    -45.13 (-58.67 to -30.84)
        Week 192 (n = 75, 151)
    -27.50 (-50.49 to -10.22)
    -43.40 (-56.45 to -28.14)
        Week 204 (n = 75, 131)
    -28.04 (-46.84 to -12.13)
    -49.71 (-60.22 to -35.16)
        Week 216 (n = 68, 98)
    -28.37 (-41.15 to -11.76)
    -44.00 (-56.69 to -31.29)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with a 15% or Greater Reduction in LDL-C

    		 Close Top of page
    End point title
    		 Percentage of Participants with a 15% or Greater Reduction in LDL-C
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216
    End point values
    		 HoFH Severe FH
    Number of subjects analysed
    106
    194
    Units: percentage of participants
    number (not applicable)
        Week 4 (n = 87, 183)
    62.1
    98.9
        Week 6 (n = 83, 166)
    51.8
    98.2
        Week 8 (n = 94, 187)
    57.4
    97.9
        Week 12 (n = 104, 191)
    56.7
    99.0
        Week 16 (n = 102, 188)
    63.7
    97.3
        Week 20 (n = 101, 185)
    64.4
    98.9
        Week 24 (n = 99, 191)
    66.7
    96.3
        Week 36 (n = 94, 187)
    62.8
    97.3
        Week 48 (n = 93, 187)
    60.2
    97.9
        Week 60 (n = 88, 186)
    60.2
    94.1
        Week 72 (n = 85, 184)
    69.4
    94.0
        Week 84 (n = 82, 180)
    65.9
    93.9
        Week 96 (n = 82, 180)
    65.9
    94.4
        Week 108 (n = 82, 181)
    61.0
    96.1
        Week 120 (n = 82, 184)
    64.6
    91.8
        Week 132 (n = 81, 177)
    61.7
    92.7
        Week 144 (n = 79, 180)
    72.2
    93.3
        Week 156 (n = 80, 181)
    68.8
    93.4
        Week 168 (n = 76, 171)
    59.2
    93.6
        Week 180 (n = 74, 166)
    63.5
    93.4
        Week 192 (n = 74, 147)
    66.2
    91.8
        Week 204 (n = 75, 129)
    65.3
    93.8
        Week 216 (n = 68, 96)
    70.6
    88.5
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug in Study 20110271 up to 30 days after the last dose or until the end of study date, whichever was earlier; median duration of treatment was 48.7 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    HoFH
    Reporting group description
    		 Participants with homozygous familial hypercholesterolemia (HoFH) received 420 mg evolocumab every month (participants not on lipid apheresis) or every 2 weeks (participants on lipid apheresis) for up to 5 years. Participants could switch dosing regimens at week 12 or 24 based on LDL-C and serum unbound proprotein convertase subtilisin/kexin type 9 (PCSK9) levels.

    Reporting group title
    Total
    Reporting group description
    		 Participants received 420 mg evolocumab every month (participants not on lipid apheresis) or every 2 weeks (participants on lipid apheresis) for up to 5 years. Participants could switch dosing regimens at week 12 or 24 based on LDL-C and serum unbound PCSK9 levels.

    Reporting group title
    Severe FH
    Reporting group description
    		 Participants with severe (non-HoFH) familial hypercholesterolemia (FH) received 420 mg evolocumab every month (participants not on lipid apheresis) or every 2 weeks (participants on lipid apheresis) for up to 5 years. Participants could switch dosing regimens at week 12 or 24 based on LDL-C and serum unbound PCSK9 levels.

    Serious adverse events
    		 HoFH Total Severe FH
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 106 (27.36%)
    86 / 300 (28.67%)
    57 / 194 (29.38%)
         number of deaths (all causes)
    2
    7
    5
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Breast cancer in situ
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Invasive lobular breast carcinoma
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian germ cell teratoma
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    3 / 106 (2.83%)
    5 / 300 (1.67%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 106 (0.94%)
    6 / 300 (2.00%)
    5 / 194 (2.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 106 (0.94%)
    4 / 300 (1.33%)
    3 / 194 (1.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 106 (1.89%)
    2 / 300 (0.67%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac stress test abnormal
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula site haemorrhage
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Tendon rupture
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 300 (0.67%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cerebrovascular arteriovenous malformation
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 106 (1.89%)
    4 / 300 (1.33%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    4 / 106 (3.77%)
    11 / 300 (3.67%)
    7 / 194 (3.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 12
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 106 (0.00%)
    3 / 300 (1.00%)
    3 / 194 (1.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    3 / 106 (2.83%)
    4 / 300 (1.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 106 (0.94%)
    5 / 300 (1.67%)
    4 / 194 (2.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supravalvular aortic stenosis
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery occlusion
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia with Lewy bodies
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 106 (0.94%)
    2 / 300 (0.67%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 106 (0.94%)
    2 / 300 (0.67%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular degeneration
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular hole
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gingival cyst
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 300 (0.67%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cyst
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-alcoholic steatohepatitis
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 106 (0.94%)
    2 / 300 (0.67%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal infarct
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 300 (0.67%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle atrophy
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Posture abnormal
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 300 (0.33%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 106 (0.94%)
    2 / 300 (0.67%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 300 (0.67%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis chronic
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 106 (0.94%)
    3 / 300 (1.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 300 (0.33%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 HoFH Total Severe FH
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    80 / 106 (75.47%)
    214 / 300 (71.33%)
    134 / 194 (69.07%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 106 (5.66%)
    9 / 300 (3.00%)
    3 / 194 (1.55%)
         occurrences all number
    13
    16
    3
    Blood creatine phosphokinase increased
         subjects affected / exposed
    6 / 106 (5.66%)
    10 / 300 (3.33%)
    4 / 194 (2.06%)
         occurrences all number
    11
    16
    5
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 106 (8.49%)
    24 / 300 (8.00%)
    15 / 194 (7.73%)
         occurrences all number
    9
    25
    16
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 106 (3.77%)
    16 / 300 (5.33%)
    12 / 194 (6.19%)
         occurrences all number
    4
    21
    17
    Headache
         subjects affected / exposed
    17 / 106 (16.04%)
    33 / 300 (11.00%)
    16 / 194 (8.25%)
         occurrences all number
    18
    41
    23
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    4 / 106 (3.77%)
    19 / 300 (6.33%)
    15 / 194 (7.73%)
         occurrences all number
    5
    21
    16
    Fatigue
         subjects affected / exposed
    8 / 106 (7.55%)
    27 / 300 (9.00%)
    19 / 194 (9.79%)
         occurrences all number
    9
    32
    23
    Influenza like illness
         subjects affected / exposed
    2 / 106 (1.89%)
    12 / 300 (4.00%)
    10 / 194 (5.15%)
         occurrences all number
    3
    15
    12
    Injection site bruising
         subjects affected / exposed
    4 / 106 (3.77%)
    14 / 300 (4.67%)
    10 / 194 (5.15%)
         occurrences all number
    6
    16
    10
    Injection site pain
         subjects affected / exposed
    6 / 106 (5.66%)
    11 / 300 (3.67%)
    5 / 194 (2.58%)
         occurrences all number
    8
    14
    6
    Oedema peripheral
         subjects affected / exposed
    3 / 106 (2.83%)
    14 / 300 (4.67%)
    11 / 194 (5.67%)
         occurrences all number
    3
    15
    12
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 106 (6.60%)
    14 / 300 (4.67%)
    7 / 194 (3.61%)
         occurrences all number
    8
    16
    8
    Diarrhoea
         subjects affected / exposed
    7 / 106 (6.60%)
    29 / 300 (9.67%)
    22 / 194 (11.34%)
         occurrences all number
    12
    40
    28
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 106 (4.72%)
    19 / 300 (6.33%)
    14 / 194 (7.22%)
         occurrences all number
    9
    23
    14
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    10 / 106 (9.43%)
    10 / 300 (3.33%)
    0 / 194 (0.00%)
         occurrences all number
    11
    11
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 106 (5.66%)
    29 / 300 (9.67%)
    23 / 194 (11.86%)
         occurrences all number
    6
    34
    28
    Back pain
         subjects affected / exposed
    9 / 106 (8.49%)
    26 / 300 (8.67%)
    17 / 194 (8.76%)
         occurrences all number
    10
    28
    18
    Muscle spasms
         subjects affected / exposed
    4 / 106 (3.77%)
    19 / 300 (6.33%)
    15 / 194 (7.73%)
         occurrences all number
    6
    31
    25
    Myalgia
         subjects affected / exposed
    6 / 106 (5.66%)
    30 / 300 (10.00%)
    24 / 194 (12.37%)
         occurrences all number
    7
    38
    31
    Pain in extremity
         subjects affected / exposed
    4 / 106 (3.77%)
    15 / 300 (5.00%)
    11 / 194 (5.67%)
         occurrences all number
    5
    18
    13
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 106 (3.77%)
    20 / 300 (6.67%)
    16 / 194 (8.25%)
         occurrences all number
    5
    30
    25
    Gastroenteritis
         subjects affected / exposed
    6 / 106 (5.66%)
    18 / 300 (6.00%)
    12 / 194 (6.19%)
         occurrences all number
    8
    21
    13
    Influenza
         subjects affected / exposed
    17 / 106 (16.04%)
    38 / 300 (12.67%)
    21 / 194 (10.82%)
         occurrences all number
    24
    47
    23
    Nasopharyngitis
         subjects affected / exposed
    17 / 106 (16.04%)
    53 / 300 (17.67%)
    36 / 194 (18.56%)
         occurrences all number
    38
    95
    57
    Sinusitis
         subjects affected / exposed
    7 / 106 (6.60%)
    14 / 300 (4.67%)
    7 / 194 (3.61%)
         occurrences all number
    9
    16
    7
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 106 (16.98%)
    35 / 300 (11.67%)
    17 / 194 (8.76%)
         occurrences all number
    39
    63
    24
    Urinary tract infection
         subjects affected / exposed
    8 / 106 (7.55%)
    20 / 300 (6.67%)
    12 / 194 (6.19%)
         occurrences all number
    11
    25
    14

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jul 2012
    • adjusted the study title to be more reflective of the actual study population • added a study acronym • clarified that laboratory data were blinded for subjects coming from a blinded (or blinded portion) of a parent study • added an optional apheresis substudy • increased the sample size from 75 subjects to 125 based on new subject interest in the study • added a screening period for either subjects who do not come from a parent study or for parent study subjects who do not roll over into Study 20110271 within 3 days • changed the dosage and dosing schedule to accommodate the eclectic subject population • updated the evolocumab background section with new data based on the phase 2 interim analysis • decreased the frequency of anti-evolocumab antibody collection after year 1 • updated the subject inclusion criteria • highlighted that any time a subject has 2 consecutive LDL-C values < 25 mg/dL, the DMC was notified. • highlighted that vitamin E values were blinded • updated the safety reporting timelines as well as the pregnancy and lactation language per Amgen’s most recent template • divided the schedule of assessments into 3 groups: rollover subjects, non-rollover non-apheresis subjects, and apheresis subjects
    07 Dec 2012
    • updated the at-home dosing information • changed the dosing terminology from Q4W to QM • added an additional secondary endpoint • added more flexible dosing language for subjects who enter Study 20110271 from Study 20110233 • highlighted that lipid lowering concomitant medications cannot be adjusted during the first 12 weeks of the study
    16 Sep 2013
    • added Lp(a) as a secondary endpoint • updated the exploratory endpoints • expanded eligible population to include patients with severe FH, without requiring HoFH or specific types of mutations • increased the sample size to 250 subjects to accommodate additional high need subjects • excluded subjects using lomitapide and CETP inhibitors • added AI/pen and AMD language • clarified dose adjustment language • updated the safety reporting section with Amgen’s new template language • added CEC language • updated the study schemas • updated the background section • added additional criteria for withholding IP • removed the apheresis substudy
    15 Apr 2014
    • updated the sample size to 310 subjects • updated the number of sites from 45 to 50 • updated the dosing language • updated the analyte table to include eGFR and serum hCG
    11 May 2015
    • removed the external DMC following the DMC’s expressed preference to not review open-label, uncontrolled safety data. • added measurements of height, weight and Tanner staging for adolescent subjects; definition of ‘adolescent’ was also provided.
    02 Dec 2015
    • clarified end of study language to specify the study will end when the last patient has completed assessments at week 260. • updated criteria for possible drug-induced liver injury. • clarified language regarding product complaints. • allowed for additional pregnancy testing at the discretion of the investigator. • corrected Tanner Staging criteria for males.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Thu May 02 11:46:26 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA