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    Clinical Trial Results:
    A Randomized, Double-Blind, Active-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of SAR236553/REGN727 over 24 weeks in Patients with Hypercholesterolemia

    Summary
    EudraCT number
    		 2011-001424-38
    Trial protocol
    		 BE   FI   NL  
    Global end of trial date
    09 Jul 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A poster - EFC11716
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01644474
    WHO universal trial number (UTN)
    		 U1111-1124-1167
    Other trial identifiers
    		 STUDY NAME: ODYSSEY MONO
    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
    03 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2013
    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) every 2 weeks (Q2W) as monotherapy in comparison with ezetimibe 10 mg daily after 24 weeks of treatment in subjects with hypercholesterolemia at moderate 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
    		 Concomitant medications were to be kept to a minimum during the study. However, if they were considered necessary for the subject’s welfare, and were unlikely to interfere with the investigational medicinal product (IMPs), they could be given at a stable dose (when possible), at the discretion of the Investigator.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jul 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
    Belgium: 15
    Country: Number of subjects enrolled
    Finland: 11
    Country: Number of subjects enrolled
    Netherlands: 28
    Country: Number of subjects enrolled
    United States: 49
    Worldwide total number of subjects
    103
    EEA total number of subjects
    54
    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)
    84
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 8 centers in 4 countries. A total of 204 subjects were screened between July 2012 and November 2012, 101 of whom were screen failures. Screen failures were mainly due to exclusion criteria met.

    Pre-assignment
    Screening details
    		 Randomization was stratified according to the diabetes mellitus status. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:1 ( alirocumab:ezetimibe) ratio after confirmation of selection criteria. 103 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 autoinjectors 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
    		 Ezetimibe 10 mg
    Arm description
    		 Oral ezetimibe 10 mg daily and subcutaneous placebo (for alirocumab) every 2 weeks (Q2W) for 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ezetimibe
    Investigational medicinal product code
    Other name
    Ezetrol
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One over-encapsulated tablet once daily.

    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.

    Arm title
    		 Alirocumab 75/Up to 150 mg Q2W
    Arm description
    		 Subcutaneous alirocumab 75 mg Q2W and oral placebo for ezetimibe for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥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
    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.

    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 capsule once daily.

    Number of subjects in period 1
    		Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Started
    51
    52
    Completed
    44
    44
    Not completed
    7
    8
         Consent withdrawn by subject
    -
    1
         'Other than specified '
    2
    1
         Adverse Event
    4
    5
         Poor compliance to protocol
    1
    -
         Patient moved
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ezetimibe 10 mg
    Reporting group description
    		 Oral ezetimibe 10 mg daily and subcutaneous placebo (for alirocumab) every 2 weeks (Q2W) for 24 weeks.

    Reporting group title
    Alirocumab 75/Up to 150 mg Q2W
    Reporting group description
    		 Subcutaneous alirocumab 75 mg Q2W and oral placebo for ezetimibe for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.

    Reporting group values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W Total
    Number of subjects
    		 51 52 103
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.6 ( 5.3 ) 60.8 ( 4.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 24 24 48
        Male
    		 27 28 55
    Calculated LDL-C in mg/dL
    Calculated LDL-C from Friedewald formula.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 138.3 ( 24.5 ) 141.1 ( 27.1 ) -
    Calculated LDL-C in mmol/L
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 3.58 ( 0.6 ) 3.65 ( 0.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Ezetimibe 10 mg
    Reporting group description
    		 Oral ezetimibe 10 mg daily and subcutaneous placebo (for alirocumab) every 2 weeks (Q2W) for 24 weeks.

    Reporting group title
    Alirocumab 75/Up to 150 mg Q2W
    Reporting group description
    		 Subcutaneous alirocumab 75 mg Q2W and oral placebo for ezetimibe for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.

    Subject analysis set title
    Ezetimibe 10 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects exposed to Ezetimibe 10 mg (mean exposure of 22 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 mg/Up to 150 mg Q2W (mean exposure of 22 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
    Calculated LDL-C values were obtained using the Friedwald formula. 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 24 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 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    51
    52
    Units: percent change
        least squares mean (standard error)
    -15.6 ( 3.1 )
    -47.2 ( 3 )
    Statistical analysis title
    		 Alirocumab vs Ezetimibe
    Statistical analysis description
    Alirocumab group was compared to ezetimibe group using an appropriate contrast statement.
    Comparison groups
    Alirocumab 75/Up to 150 mg Q2W v Ezetimibe 10 mg
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -31.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.2
         upper limit
    		 -23
    Notes
    [1] - Threshold for significance was ≤ 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 MMRM including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment (ITT analysis). ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    51
    52
    Units: percent change
        least squares mean (standard error)
    -19.6 ( 2.6 )
    -48.1 ( 2.6 )
    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
    Ezetimibe 10 mg v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -28.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35.7
         upper limit
    		 -21.2
    Notes
    [2] - 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 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline Apo B value on- or off-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    46
    48
    Units: percent change
        least squares mean (standard error)
    -11 ( 2.4 )
    -36.7 ( 2.3 )
    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
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -25.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.3
         upper limit
    		 -19.2
    Notes
    [3] - 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 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline non-HDL-C value on- or off-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    51
    52
    Units: percent change
        least squares mean (standard error)
    -15.1 ( 2.9 )
    -40.6 ( 2.8 )
    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
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -25.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.5
         upper limit
    		 -17.4
    Notes
    [4] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Total Cholestrol (Total-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 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline Total-C value on- or off-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    51
    52
    Units: percent change
        least squares mean (standard error)
    -10.9 ( 2.2 )
    -29.6 ( 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
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -18.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.7
         upper limit
    		 -12.7
    Notes
    [5] - 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 24 regardless of status on- or off-treatment. Apo B ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    46
    48
    Units: percent change
        least squares mean (standard error)
    -11.7 ( 2.1 )
    -37.3 ( 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
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -25.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.5
         upper limit
    		 -19.8
    Notes
    [6] - 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 24 regardless of status on- or off-treatment. non-HDL-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    51
    52
    Units: percent change
        least squares mean (standard error)
    -16.7 ( 2.4 )
    -42.5 ( 2.3 )
    Statistical analysis title
    		 Alirocumab vs Ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Ezetimibe 10 mg v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -25.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.4
         upper limit
    		 -19.2
    Notes
    [7] - Threshold for significance ≤ 0.05.

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

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    End point title
    		 Percent Change From Baseline in Total Cholestrol (Total-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 24 regardless of status on- or off-treatment. Total-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    51
    52
    Units: percent change
        least squares mean (standard error)
    -12 ( 1.7 )
    -30.3 ( 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
    Ezetimibe 10 mg v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -18.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.1
         upper limit
    		 -13.5
    Notes
    [8] - Threshold for significance ≤ 0.05.

    Secondary: Percentage of Subjects Achieving Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis

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    End point title
    		 Percentage of Subjects Achieving Calculated LDL-C <100 mg/dL (2.59 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 24 regardless of status on- or off-treatment were included in the imputation model (ITT analysis). ITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    51
    52
    Units: percentage of subjects
        number (not applicable)
    32.2
    88.1
    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
    Ezetimibe 10 mg v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    34.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.7
         upper limit
    		 139
    Notes
    [9] - 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 from multiple imputation approach including all available post-baseline data from Week 4 to Week 24 regardless of status on­- or off-­treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    51
    52
    Units: percentage of subjects
        number (not applicable)
    2.4
    59.4
    Statistical analysis title
    		 Alirocumab vs Ezetimibe
    Statistical analysis description
    Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).
    Comparison groups
    Ezetimibe 10 mg v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [10]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    69.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.8
         upper limit
    		 556
    Notes
    [10] - Threshold for significance was ≤ 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 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    51
    52
    Units: percent change
        arithmetic mean (standard error)
    -12.3 ( 3.8 )
    -16.7 ( 3.7 )
    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
    Ezetimibe 10 mg v Alirocumab 75/Up to 150 mg Q2W
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4013 [11]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.8
         upper limit
    		 5.9
    Notes
    [11] - Threshold for significance was ≤ 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 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline HDL-C value on- or off-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    51
    52
    Units: percent change
        least squares mean (standard error)
    1.6 ( 1.9 )
    6 ( 1.9 )
    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 24 regardless of status on- or off-treatment. HDL-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    51
    52
    Units: percent change
        least squares mean (standard error)
    1.6 ( 2 )
    9 ( 2 )
    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 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    51
    52
    Units: percent change
        arithmetic mean (standard error)
    -14.2 ( 3.7 )
    -17.2 ( 3.7 )
    No statistical analyses for this end point

    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 multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    51
    52
    Units: percent change
        arithmetic mean (standard error)
    -10.8 ( 4.3 )
    -11.9 ( 4.2 )
    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 multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Fasting triglycerides ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    51
    52
    Units: percent change
        arithmetic mean (standard error)
    -2.3 ( 3.5 )
    -12.2 ( 3.4 )
    No statistical analyses for this end point

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

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    End point title
    		 Percent Change From Baseline in Apoprotein 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 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline Apo A-1 value on- or off-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    46
    48
    Units: percent change
        least squares mean (standard error)
    -0.6 ( 1.6 )
    4.7 ( 1.6 )
    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 24 regardless of status on- or off-treatment. Apo A-1 ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Number of subjects analysed
    46
    48
    Units: percent change
        arithmetic mean (standard error)
    -2.2 ( 1.4 )
    2.3 ( 1.4 )
    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 the final visit (Week 32) regardless of seriousness or relationship to investigational medicinal product (IMP).
    Adverse event reporting additional description
    Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the ‘treatment-emergent period’ (from the first dose of double-blind 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
    16.0
    Reporting groups
    Reporting group title
    Ezetimibe 10 mg
    Reporting group description
    		 Subjects exposed to Ezetimibe 10 mg (mean exposure of 22 weeks).

    Reporting group title
    Alirocumab 75/Up to 150 mg Q2W
    Reporting group description
    		 Subjects exposed to Alirocumab 75 mg/Up to 150 mg Q2W (mean exposure of 22 weeks).

    Serious adverse events
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 52 (1.92%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Embolism
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone Erosion
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (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
    		 Ezetimibe 10 mg Alirocumab 75/Up to 150 mg Q2W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 51 (52.94%)
    25 / 52 (48.08%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1
    Headache
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 52 (5.77%)
         occurrences all number
    2
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 51 (3.92%)
    6 / 52 (11.54%)
         occurrences all number
    2
    6
    Nausea
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 52 (5.77%)
         occurrences all number
    3
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 52 (5.77%)
         occurrences all number
    2
    3
    Back Pain
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 52 (1.92%)
         occurrences all number
    3
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    3 / 51 (5.88%)
    6 / 52 (11.54%)
         occurrences all number
    3
    6
    Nasopharyngitis
         subjects affected / exposed
    8 / 51 (15.69%)
    12 / 52 (23.08%)
         occurrences all number
    9
    16
    Upper Respiratory Tract Infection
         subjects affected / exposed
    5 / 51 (9.80%)
    2 / 52 (3.85%)
         occurrences all number
    6
    2
    Urinary Tract Infection
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 52 (0.00%)
         occurrences all number
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Feb 2013
    1. Change in reporting of adverse events - safety reporting timelines was changed from “within 1 working day” to “within 24 hours” for serious adverse events and adverse events of special interest (AESI) with immediate notification. - Addition of pregnancy of male subject’s partner as an AESI with immediate notification. 2. Clarification for some safety laboratory parameters - Red blood cell distribution width and reticulocyte count added as hematology laboratory parameters. - Reticulocyte count no longer assessed reflexively but rather systematically on all study samples. 3. Precision added in the definition of the investigational medicinal product – ezetimibe capsule. 4. Highlighted the need for an effective method of contraception in women of childbearing potential throughout the study treatment.

    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.
    Due to administrative error in the automated process (which was detected after database lock), planned dose up-titration criteria for LDL-C levels was changed from ≥100 mg/dL to ≥70 mg/dL.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25606700
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