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    Clinical Trial Results:
    A Randomized, Double-Blind, Parallel Group Study to Evaluate the Efficacy and Safety of SAR236553/REGN727 Versus Ezetimibe in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Statin Therapy

    Summary
    EudraCT number
    		 2011-004130-34
    Trial protocol
    		 HU   DK   DE  
    Global end of trial date
    28 Jul 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Addition of results: analysis of efficacy data at time points beyond the Week 52 time point (primary completion) as well as final analysis of safety data at the end of the study (Week 112)

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC11569
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01644188
    WHO universal trial number (UTN)
    		 U1111-1121-4315
    Other trial identifiers
    		 Study name: ODYSSEY COMBO II
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab (SAR236553/REGN727) as add-on therapy to stable maximally tolerated daily statin therapy in comparison with ezetimibe 10 mg after 24 weeks of treatment in subjects with hypercholesterolemia at high cardiovascular (CV) risk.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates
    Background therapy
    		 All subjects had to receive a statin at maximally tolerated dose (simvastatin, atorvastatin and rosuvastatin). Background statin therapy was not to be changed (including dose) at least 4 weeks prior to the screening visit and throughout the whole study duration barring exceptional circumstances.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Aug 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: 17
    Country: Number of subjects enrolled
    Israel: 23
    Country: Number of subjects enrolled
    Korea, Republic of: 42
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Hungary: 65
    Country: Number of subjects enrolled
    Denmark: 100
    Country: Number of subjects enrolled
    Russian Federation: 149
    Country: Number of subjects enrolled
    South Africa: 92
    Country: Number of subjects enrolled
    Ukraine: 6
    Country: Number of subjects enrolled
    United States: 217
    Worldwide total number of subjects
    720
    EEA total number of subjects
    174
    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)
    434
    From 65 to 84 years
    282
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 126 centers in 10 countries. Overall, 1112 subjects were screened between August 2012 and May 2013, 392 of whom were screen failures. Screen failures ware mainly due to exclusion criteria met.

    Pre-assignment
    Screening details
    		 Randomization was stratified according to prior history of myocardial infarction (MI) or ischemic stroke, intensity of statin treatment and geographical region. Assignment to arms was done centrally using Interactive Voice/Web Response System in 2:1 ratio (alirocumab: ezetimibe) after confirmation of selection criteria. 720 subjects were randomized

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    Alirocumab and placebo for alirocumab were provided in identically matched auto-injectors and packaged identically. Ezetimibe double-blind treatment kit boxes, either ezetimibe 10 mg or placebo for ezetimibe, had the same appearance and feel and were labeled with a double-blind label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Alirocumab 75/up to 150 mg Q2W
    Arm description
    		 Subcutaneous alirocumab 75 mg every 2 weeks (Q2W) and oral placebo for ezetimibe daily added to stable Lipid-Modifying Therapy (LMT) for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    SAR236553, REGN727
    Other name
    Praluent
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 mL subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using the auto-injector.

    Investigational medicinal product name
    Placebo (for Ezetimibe)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One over-encapsulated tablet once daily at approximately the same time of the day with or without food.

    Arm title
    		 Ezetimibe 10 mg
    Arm description
    		 Oral ezetimibe 10 mg daily and subcutaneous placebo for alirocumab Q2W added to stable LMT for 104 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ezetimibe
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One over-encapsulated tablet once daily at approximately the same time of the day with or without food.

    Investigational medicinal product name
    Placebo (for alirocumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 mL subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using the auto-injector.

    Number of subjects in period 1
    		Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Started
    479
    241
    Treated
    479
    241
    Completed
    357
    166
    Not completed
    122
    75
         Last visit outside protocol visit window
    14
    16
         Related to Auto-injector Administration
    2
    2
         Physician decision
    1
    3
         Consent withdrawn by subject
    14
    7
         Lost to follow-up
    1
    -
         Selection criteria finally not met
    2
    -
         Death
    4
    3
         Adverse event
    44
    20
         Other than specified
    6
    7
         Subject moved
    7
    2
         Poor compliance to protocol
    26
    14
         Site closure
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alirocumab 75/up to 150 mg Q2W
    Reporting group description
    		 Subcutaneous alirocumab 75 mg every 2 weeks (Q2W) and oral placebo for ezetimibe daily added to stable Lipid-Modifying Therapy (LMT) for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.

    Reporting group title
    Ezetimibe 10 mg
    Reporting group description
    		 Oral ezetimibe 10 mg daily and subcutaneous placebo for alirocumab Q2W added to stable LMT for 104 weeks.

    Reporting group values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg Total
    Number of subjects
    		 479 241 720
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.7 ( 9.4 ) 61.3 ( 9.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 119 71 190
        Male
    		 360 170 530
    Calculated LDL-C in mg/dL
    Calculated LDL-­C in mg/dL from Friedewald formula (LDL cholesterol = Total cholesterol – HDL cholesterol ­ [Triglyceride/5]).
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 108.6 ( 36.5 ) 104.6 ( 34.1 ) -
    Calculated LDL-C in mmol/L
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 2.812 ( 0.945 ) 2.71 ( 0.884 ) -

    End points

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    End points reporting groups
    Reporting group title
    Alirocumab 75/up to 150 mg Q2W
    Reporting group description
    		 Subcutaneous alirocumab 75 mg every 2 weeks (Q2W) and oral placebo for ezetimibe daily added to stable Lipid-Modifying Therapy (LMT) for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.

    Reporting group title
    Ezetimibe 10 mg
    Reporting group description
    		 Oral ezetimibe 10 mg daily and subcutaneous placebo for alirocumab Q2W added to stable LMT for 104 weeks.

    Subject analysis set title
    Alirocumab 75 /up to 150 mg Q2W
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects exposed to Alirocumab 75 /up to 150 mg Q2W added to stable LMT (mean exposure of 58 weeks).

    Subject analysis set title
    Ezetimibe 10 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects exposed to Ezetimibe 10 mg added to stable LMT (mean exposure of 58 weeks).

    Primary: Percent Change From Baseline in Calculated LDL-C at Week 24 -Intent-to-treat (ITT) Analysis

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 24 -Intent-to-treat (ITT) Analysis
    End point description
    Adjusted Least-squares (LS) means and standard errors at Week 24 were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data. All available post-baseline data from week 4 to week 52 regardless of status on- or off-treatment were used in the model (ITT analysis). ITT population: all randomized subjects with one baseline and at least one post-baseline calculated LDL-C value on- or off-treatment.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: percent change
        least squares mean (standard error)
    -50.6 ( 1.4 )
    -20.7 ( 1.9 )
    Statistical analysis title
    		 Alirocumab vs. Ezetimibe
    Statistical analysis description
    Alirocumab group was compared to ezetimibe group using an appropriate contrast statement.
    Comparison groups
    Ezetimibe 10 mg v Alirocumab 75/up to 150 mg Q2W
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -29.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.4
         upper limit
    		 -25.3
    Notes
    [1] - Threshold for significance ≤0.05

    Secondary: Percent Change From Baseline in Calculated LDL-C at Week 24 - On-treatment Analysis

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 24 - On-treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first). Modified ITT population (mITT): all randomized and treated subjects with one baseline and at least one post-baseline calculated LDL-C value on-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    464
    235
    Units: percent change
        least squares mean (standard error)
    -52.4 ( 1.3 )
    -21.8 ( 1.8 )
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    699
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -30.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.9
         upper limit
    		 -26.2
    Notes
    [2] - Threshold for significance ≤0.05

    Secondary: Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT analysis

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from a MMRM including all available post-baseline data from week 4 to week 52 regardless of status on- or off-treatment (ITT analysis). ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: percent change
        least squares mean (standard error)
    -51.2 ( 1.3 )
    -21.8 ( 1.8 )
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -29.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.7
         upper limit
    		 -25.1
    Notes
    [3] - Threshold for significance ≤0.05

    Secondary: Percent Change from Baseline in Calculated LDL-C at Week 12 - On-treatment analysis

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    End point title
    		 Percent Change from Baseline in Calculated LDL-C at Week 12 - On-treatment analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first). mITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    464
    235
    Units: percent change
        least squares mean (standard error)
    -52.4 ( 1.2 )
    -22.7 ( 1.7 )
    Statistical analysis title
    		 Alirocumab vs Ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    699
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -29.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.8
         upper limit
    		 -25.6
    Notes
    [4] - Threshold for significance <0.05 

    Secondary: Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24 - ITT analysis

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24 - ITT analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline Apo B value on- or off-treatment (Apo B ITT population).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    452
    228
    Units: percent change
        least squares mean (standard error)
    -40.7 ( 1.1 )
    -18.3 ( 1.5 )
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    680
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -22.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26
         upper limit
    		 -18.8
    Notes
    [5] - Threshold for significance ≤0.05

    Secondary: Percent Change From Baseline in Apo B at Week 24 - On-treatment analysis

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    End point title
    		 Percent Change From Baseline in Apo B at Week 24 - On-treatment analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first). Subjects of the mITT population with one baseline and at least one post-baseline Apo B value on-treatment (Apo B mITT population).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    442
    221
    Units: percent change
        least squares mean (standard error)
    -42.1 ( 1 )
    -19.1 ( 1.4 )
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.5
         upper limit
    		 -19.6
    Notes
    [6] - Threshold for significance ≤0.05

    Secondary: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis

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    End point title
    		 Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline non-HDL-C value on- or off-treatment (non-HDL-C ITT population).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: percent change
        least squares mean (standard error)
    -42.1 ( 1.2 )
    -19.2 ( 1.7 )
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -22.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.9
         upper limit
    		 -18.9
    Notes
    [7] - Threshold for significance ≤0.05.

    Secondary: Percent Change From Baseline in Non-HDL-C at Week 24 - On-treatment Analysis

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    End point title
    		 Percent Change From Baseline in Non-HDL-C at Week 24 - On-treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first). Subjects of the mITT population with one baseline and at least one post-baseline Non-HDL-C value on-treatment (non-HDL-C mITT population).
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    464
    235
    Units: percent change
        least squares mean (standard error)
    -43.7 ( 1.1 )
    -20.2 ( 1.6 )
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    699
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -23.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.2
         upper limit
    		 -19.7
    Notes
    [8] - Threshold for significance ≤0.05

    Secondary: Percent Change From Baseline in Total Cholesterol (TC) at Week 24 - ITT Analysis

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    End point title
    		 Percent Change From Baseline in Total Cholesterol (TC) at Week 24 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline TC value on- or off-treatment (total-C ITT population).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: percent change
        least squares mean (standard error)
    -29.3 ( 0.9 )
    -14.6 ( 1.2 )
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -14.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.7
         upper limit
    		 -11.7
    Notes
    [9] - Threshold for significance ≤0.05.

    Secondary: Percent Change From Baseline in Apo-B at Week 12 - ITT analysis

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    End point title
    		 Percent Change From Baseline in Apo-B at Week 12 - ITT analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Apo-B ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    452
    228
    Units: percent change
        least squares mean (standard error)
    -39.7 ( 1 )
    -17.2 ( 1.3 )
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    680
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -22.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.7
         upper limit
    		 -19.2
    Notes
    [10] - Threshold for significance ≤0.05.

    Secondary: Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis

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    End point title
    		 Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Non-HDL-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: percent change
        least squares mean (standard error)
    -42.6 ( 1.1 )
    -20.6 ( 1.5 )
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.6
         upper limit
    		 -18.3
    Notes
    [11] - Threshold for significance ≤0.05

    Secondary: Percent Change From Baseline in Total Cholesterol (TC) at Week 12 - ITT Analysis

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    End point title
    		 Percent Change From Baseline in Total Cholesterol (TC) at Week 12 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Total-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: percent change
        least squares mean (standard error)
    -29.4 ( 0.8 )
    -15.1 ( 1.1 )
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -14.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.1
         upper limit
    		 -11.6
    Notes
    [12] - Threshold for significance ≤0.05

    Secondary: Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 52 from a MMRM model including all available post-baseline data from week 4 to week 52 regardless of status on- or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: percent change
        least squares mean (standard error)
    -49.5 ( 1.5 )
    -18.3 ( 2.1 )
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [13]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -31.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.3
         upper limit
    		 -26.1
    Notes
    [13] - Threshold for significance ≤0.05

    Secondary: Percentage of Subjects Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT analysis

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    End point title
    		 Percentage of Subjects Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT analysis
    End point description
    Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from week 4 to week 52 regardless of status on- or off-treatment were included in the imputation model. ITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: percentage of subjects
        number (not applicable)
    77
    45.6
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a Logistic regression model
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [14]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.7
         upper limit
    		 7.9
    Notes
    [14] - Threshold for significance ≤0.05

    Secondary: Percentage of Subjects Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-treatment analysis

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    End point title
    		 Percentage of Subjects Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-treatment analysis
    End point description
    Adjusted percentages at Week 24 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from week 4 to week 52 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first). mITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    464
    235
    Units: percentage of subjects
        number (not applicable)
    78.9
    47.4
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    699
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [15]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.9
         upper limit
    		 8.8
    Notes
    [15] - Threshold for significance ≤0.05

    Secondary: Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT analysis

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    End point title
    		 Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT analysis
    End point description
    Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: percent change
        arithmetic mean (standard error)
    -27.8 ( 1.4 )
    -6.1 ( 2 )
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a robust regression model
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [16]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -21.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.4
         upper limit
    		 -17
    Notes
    [16] - Threshold for significance ≤0.05

    Secondary: Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis

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    End point title
    		 Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline HDL-C value on- or off-treatment(HDL-C ITT population).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: percent change
        least squares mean (standard deviation)
    8.6 ( 0.8 )
    0.5 ( 1.1 )
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [17]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    8.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.4
         upper limit
    		 10.7
    Notes
    [17] - Threshold for significance ≤0.05

    Secondary: Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis

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    End point title
    		 Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
    End point description
    Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: percent change
        arithmetic mean (standard error)
    -13 ( 1.5 )
    -12.8 ( 2 )
    Statistical analysis title
    		 Alirocumab vs. ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Alirocumab 75/up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    707
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9117 [18]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.1
         upper limit
    		 4.6
    Notes
    [18] - Threshold for significance ≤0.05

    Secondary: Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24 - ITT Analysis

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    End point title
    		 Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline Apo A-1 value on- or off-treatment (Apo A-1 ITT population).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    452
    228
    Units: percent change
        least squares mean (standard error)
    5 ( 0.6 )
    -1.3 ( 0.8 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Lipoprotein(a) at Week 12 - ITT analysis

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    End point title
    		 Percent Change From Baseline in Lipoprotein(a) at Week 12 - ITT analysis
    End point description
    Adjusted means and standard errors at Week 12 from from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: percent change
        arithmetic mean (standard error)
    -22.1 ( 1.2 )
    1.1 ( 1.7 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis

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    End point title
    		 Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. HDL-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: percent change
        least squares mean (standard error)
    8.7 ( 0.7 )
    2.8 ( 1 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis

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    End point title
    		 Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis
    End point description
    Adjusted means and standard errors at Week 12 from from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: percent change
        arithmetic mean (standard error)
    -13 ( 1.5 )
    -12.8 ( 2 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis

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    End point title
    		 Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. Apo A-1 ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75/up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: percent change
        least squares mean (standard error)
    1.5 ( 0.5 )
    -2.9 ( 0.7 )
    No statistical analyses for this end point

    Other pre-specified: Percent Change From Baseline in Calculated LDL-C at Week 52 – On-Treatment Analysis

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 52 – On-Treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 52 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first). mITT population.
    End point type
    Other pre-specified
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Alirocumab 75 /up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    464
    235
    Units: Percent change
        least squares mean (standard error)
    -51.8 ( 1.5 )
    -19.7 ( 2.1 )
    No statistical analyses for this end point

    Other pre-specified: Percent Change From Baseline in Calculated LDL-C at Week 104 – ITT Analysis

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 104 – ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 104 from MMRM including all available post-baseline data from Week 4 to Week 104 regardless of status on- or off-treatment. ITT population.
    End point type
    Other pre-specified
    End point timeframe
    From Baseline to Week 104
    End point values
    		 Alirocumab 75 /up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    467
    240
    Units: Percent change
        least squares mean (standard error)
    -44.2 ( 1.7 )
    -15.2 ( 2.4 )
    No statistical analyses for this end point

    Other pre-specified: Percent Change From Baseline in Calculated LDL-C at Week 104 – On-Treatment Analysis

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 104 – On-Treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 104 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 104 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first). mITT population.
    End point type
    Other pre-specified
    End point timeframe
    From Baseline to Week 104
    End point values
    		 Alirocumab 75 /up to 150 mg Q2W Ezetimibe 10 mg
    Number of subjects analysed
    464
    235
    Units: Percent change
        least squares mean (standard error)
    -48.9 ( 1.7 )
    -17 ( 2.4 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs.
    Adverse event reporting additional description
    Reported AEs and deaths are treatment-emergent that is AEs that developed/worsened and deaths that occurred during 'the treatment-emergent period’ (from the first dose of double-blind investigational medicinal product (IMP) administration [capsule or injection, whichever came first] up the day of the last double-blind IMP injection + 70 days).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Alirocumab 75 /Up to 150 mg Q2W
    Reporting group description
    		 Subjects exposed to Alirocumab 75 /up to 150 mg Q2W added to stable LMT (mean exposition of 90 weeks).

    Reporting group title
    Ezetimibe 10 mg
    Reporting group description
    		 Subjects exposed to Ezetimibe 10 mg added to stable LMT (mean exposition of 90 weeks).

    Serious adverse events
    		 Alirocumab 75 /Up to 150 mg Q2W Ezetimibe 10 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    124 / 479 (25.89%)
    60 / 241 (24.90%)
         number of deaths (all causes)
    6
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Chronic Lymphocytic Leukaemia
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Stromal Tumour
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Adenocarcinoma
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases To Central Nervous System
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-Small Cell Lung Cancer
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-Small Cell Lung Cancer Metastatic
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-Small Cell Lung Cancer Stage Iiia
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal Carcinoma
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oestrogen Receptor Positive Breast Cancer
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic Carcinoma
         subjects affected / exposed
    2 / 479 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pituitary Tumour Benign
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    3 / 479 (0.63%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Neoplasm
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma Of Lung
         subjects affected / exposed
    1 / 479 (0.21%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Squamous Cell Carcinoma Of Skin
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic Dissection
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Femoral Artery Occlusion
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 479 (0.63%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    2 / 479 (0.42%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Artery Aneurysm
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Vascular Disorder
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis Superficial
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous Thrombosis Limb
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    2 / 479 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implant Site Haematoma
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    6 / 479 (1.25%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden Cardiac Death
         subjects affected / exposed
    1 / 479 (0.21%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Sudden Death
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    4 / 479 (0.84%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic Pain
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep Apnoea Syndrome
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal Cord Polyp
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed Suicide
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Confusional State
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Bacterial Test Positive
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International Normalised Ratio Increased
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Restenosis
         subjects affected / exposed
    1 / 479 (0.21%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula Fracture
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand Fracture
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional Hernia
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus Injury
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Fractures
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella Fracture
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis Fracture
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skeletal Injury
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    12 / 479 (2.51%)
    3 / 241 (1.24%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    10 / 479 (2.09%)
    6 / 241 (2.49%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    9 / 479 (1.88%)
    6 / 241 (2.49%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis Coronary Artery
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    4 / 479 (0.84%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    2 / 479 (0.42%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block Complete
         subjects affected / exposed
    2 / 479 (0.42%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block Second Degree
         subjects affected / exposed
    1 / 479 (0.21%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    4 / 479 (0.84%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    2 / 479 (0.42%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    4 / 479 (0.84%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic Shock
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Congestive Cardiomyopathy
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 479 (0.21%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Defect Conduction Intraventricular
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial Infarction
         subjects affected / exposed
    3 / 479 (0.63%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    1 / 479 (0.21%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Silent Myocardial Infarction
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Extrasystoles
         subjects affected / exposed
    0 / 479 (0.00%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Fibrillation
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Tachycardia
         subjects affected / exposed
    2 / 479 (0.42%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain Injury
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid Artery Disease
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid Artery Stenosis
         subjects affected / exposed
    2 / 479 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Haemorrhage
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrosclerosis
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia Alzheimer's Type
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 479 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial Paresis
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-Ischaemic Encephalopathy
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intracranial Aneurysm
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    3 / 479 (0.63%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss Of Consciousness
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelitis Transverse
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sensory Disturbance
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 479 (0.42%)
    4 / 241 (1.66%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Global Amnesia
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    3 / 479 (0.63%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 479 (0.42%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic Anaemia
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Cupulolithiasis
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 479 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract Nuclear
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmoplegia
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal Detachment
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vision Blurred
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Hernia
         subjects affected / exposed
    2 / 479 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular Perforation
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum Intestinal
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Haemorrhage
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Ulcer Haemorrhage
         subjects affected / exposed
    3 / 479 (0.63%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 479 (0.21%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroduodenitis
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    2 / 479 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    3 / 479 (0.63%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritable Bowel Syndrome
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Intestine Polyp
         subjects affected / exposed
    2 / 479 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 479 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 479 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis Acute
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema Nummular
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    2 / 479 (0.42%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus Ureteric
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 479 (0.42%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Tubular Necrosis
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 479 (0.21%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 479 (0.42%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Compartment Syndrome
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank Pain
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    3 / 479 (0.63%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator Cuff Syndrome
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Column Stenosis
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Instability
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Osteoarthritis
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis Infective
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 479 (0.21%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis Of Male External Genital Organ
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic Abscess
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    3 / 479 (0.63%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myringitis Bullous
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis Chronic
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 479 (1.88%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Staphylococcal
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative Wound Infection
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scrotal Abscess
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal Bacteraemia
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound Infection
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Alirocumab 75 /Up to 150 mg Q2W Ezetimibe 10 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    185 / 479 (38.62%)
    90 / 241 (37.34%)
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    47 / 479 (9.81%)
    19 / 241 (7.88%)
         occurrences all number
    70
    33
    Vascular disorders
    Hypertension
         subjects affected / exposed
    31 / 479 (6.47%)
    14 / 241 (5.81%)
         occurrences all number
    38
    19
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    28 / 479 (5.85%)
    18 / 241 (7.47%)
         occurrences all number
    29
    20
    Headache
         subjects affected / exposed
    29 / 479 (6.05%)
    13 / 241 (5.39%)
         occurrences all number
    36
    14
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    25 / 479 (5.22%)
    13 / 241 (5.39%)
         occurrences all number
    28
    14
    Infections and infestations
    Influenza
         subjects affected / exposed
    22 / 479 (4.59%)
    16 / 241 (6.64%)
         occurrences all number
    25
    17
    Nasopharyngitis
         subjects affected / exposed
    23 / 479 (4.80%)
    15 / 241 (6.22%)
         occurrences all number
    35
    16
    Upper Respiratory Tract Infection
         subjects affected / exposed
    42 / 479 (8.77%)
    17 / 241 (7.05%)
         occurrences all number
    52
    20

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Feb 2013
    - Changes in the exclusion criteria related to diabetic control status, history of human immunodeficiency virus, previous participation in any clinical trial of alirocumab or any other anti-PCSK9 monoclonal antibody, laboratory findings during the screening period, and known hypersensitivity to monoclonal antibody. - Change in the reporting of AEs. - Change in the screening period duration and the window for the training visit. - Added the information on a possible contingency strategy in the event the manufacturer faces any performance or supply issues of the auto-injector in order to ensure the continuity of the study treatment without interruption. - Clarification for some safety laboratory parameters. - Clarification was provided regarding the type of cardiovascular (CV) events to be submitted to the Clinical Events Committee (CEC) for adjudication - Added a new section of contraception in the Concomitant medication section. - Precision in the definition of IMP and the way of handling treatment interruption. - Added information on the collection of family medical history to be consistent with what was collected in the e-CRF and with regard to the population enrolled in the study.
    26 Feb 2014
    - Statistical section was changed. - Addition of the blinding procedures related to pharmacokinetic analysis. - Updated language on cardiovascular events to be reported to the CEC for adjudication and including a clarification on cerebrovascular events. - Added the following sentence “LDL-C was also be measured (via the beta-quantification method) at Week 0 and Week 24”. - Updated language on collection of information on partner pregnancy as per other protocol in the ODYSSEY phase 3 program. - Updated language on how to record injection site reactions that were not related to study drug. - Categorization of AEs: updated language on how to record injection site reactions that were not related to study drug.

    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.
    Manual reclassification was done by the Sponsor for the "other reasons" of non-completion of study as specified in the electronic case report form (eCRF).

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25687353
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