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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia Undergoing Lipid Apheresis Therapy

    Summary
    EudraCT number
    		 2014-001917-20
    Trial protocol
    		 DE  
    Global end of trial date
    20 Apr 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    R727-CL-1216
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02326220
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Study name: ODYSSEY ESCAPE
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Rd., Tarrytown, United States,
    Public contact
    Clinical Trials information, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trials information, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.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
    31 Aug 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the effect of alirocumab 150 mg every 2 weeks (Q2W) in comparison with placebo on the frequency of low-density lipoprotein (LDL) apheresis treatments in subjects with heterozygous familial hypercholesterolemia (HeFH) undergoing weekly or bi-weekly LDL apheresis therapy.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 Subjects undergoing LDL apheresis therapy every 1 or 2 weeks were enrolled in this study while maintaining background lipid modifying therapy (LMT) treatment throughout the study. All patients were being treated with the maximally tolerated clinically-relevant LMT.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Mar 2015
    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
    Germany: 30
    Country: Number of subjects enrolled
    United States: 32
    Worldwide total number of subjects
    62
    EEA total number of subjects
    30
    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)
    41
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in Germany and the United States between 09 Mar 2015 and 20 Apr 2016. A total of 76 subjects were screened, of which 62 were enrolled and randomized in the study.

    Pre-assignment
    Screening details
    		 Randomization was stratified according to the frequency of the apheresis procedure (every 7 or 14 days) and Lipoprotein (a) (Lp [a]) levels (normal or elevated). Assignment to treatment arms was done using an Interactive Voice/Web Response System in 1:2 ratio to placebo or alirocumab 150 mg Q2W.

    Period 1
    Period 1 title
    Double-blind Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo Q2W
    Arm description
    		 Placebo (for alirocumab) subcutaneous (SC) injection Q2W up to Week 16. Apheresis frequency was fixed (weekly or bi-weekly) until Week 6, then it was adjusted according to the response to treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    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.

    Arm title
    		 Alirocumab 150 mg Q2W
    Arm description
    		 Alirocumab 150 mg subcutaneous (SC) injection Q2W up to Week 16. Apheresis frequency was fixed (weekly or bi-weekly) until Week 6, then it was adjusted according to the response to treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    SAR236553, REGN727
    Other name
    Praluent®
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    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
    		Placebo Q2W Alirocumab 150 mg Q2W
    Started
    21
    41
    Completed
    20
    37
    Not completed
    1
    4
         Consent withdrawn by subject
    -
    1
         Adverse events
    1
    2
         Poor compliance to protocol
    -
    1
    Period 2
    Period 2 title
    Open-label Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Alirocumab 150 mg Q2W
    Arm description
    		 Alirocumab 150 mg SC injection Q2W starting from Week 18 up to Week 76 or until alirocumab became commercially available in the subject’s country, whichever occurred first. Apheresis treatment was not required in the open-label treatment period and could be stopped or continued at the investigator’s discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    SAR236553, REGN727
    Other name
    Praluent®
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    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 2 [1]
    		Alirocumab 150 mg Q2W
    Started
    29
    Completed
    27
    Not completed
    2
         Consent withdrawn by subject
    1
         Lost to follow-up
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Entry into the open-label treatment period was available only to patients who were study participants in a country in which alirocumab was not commercially available.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo Q2W
    Reporting group description
    		 Placebo (for alirocumab) subcutaneous (SC) injection Q2W up to Week 16. Apheresis frequency was fixed (weekly or bi-weekly) until Week 6, then it was adjusted according to the response to treatment.

    Reporting group title
    Alirocumab 150 mg Q2W
    Reporting group description
    		 Alirocumab 150 mg subcutaneous (SC) injection Q2W up to Week 16. Apheresis frequency was fixed (weekly or bi-weekly) until Week 6, then it was adjusted according to the response to treatment.

    Reporting group values
    		 Placebo Q2W Alirocumab 150 mg Q2W Total
    Number of subjects
    		 21 41 62
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57 ± 10.5 59.5 ± 9.2 -
    Gender categorical
    Units: Subjects
        Female
    		 11 15 26
        Male
    		 10 26 36
    Race
    Units: Subjects
        White
    		 21 39 60
        Black or African American
    		 0 2 2
        Asian
    		 0 0 0
        American Indian or Alaska Native
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Other
    		 0 0 0
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 21 41 62
    Frequency in which Subjects are Undergoing Apheresis
    Units: Subjects
        Every week
    		 9 18 27
        Every 2 weeks
    		 12 23 35
    Lipoprotein (a) in mg/dL
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 45.7 ± 49.5 43 ± 54.5 -
    Lipoprotein (a) in g/L
    Units: g/L
        arithmetic mean (standard deviation)
    		 0.457 ± 0.495 0.43 ± 0.545 -
    Calculated LDL-C in mg/dL
    Calculated LDL-C from Friedewald formula (LDL-C = Total cholesterol [Total-C] - High-Density Lipoprotein Cholesterol [HDL-C] - [Triglyceride/5]).
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 191.6 ± 68.9 175.1 ± 54.6 -
    Calculated LDL-C in mmol/L
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 4.964 ± 1.783 4.534 ± 1.413 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo Q2W
    Reporting group description
    		 Placebo (for alirocumab) subcutaneous (SC) injection Q2W up to Week 16. Apheresis frequency was fixed (weekly or bi-weekly) until Week 6, then it was adjusted according to the response to treatment.

    Reporting group title
    Alirocumab 150 mg Q2W
    Reporting group description
    		 Alirocumab 150 mg subcutaneous (SC) injection Q2W up to Week 16. Apheresis frequency was fixed (weekly or bi-weekly) until Week 6, then it was adjusted according to the response to treatment.
    Reporting group title
    Alirocumab 150 mg Q2W
    Reporting group description
    		 Alirocumab 150 mg SC injection Q2W starting from Week 18 up to Week 76 or until alirocumab became commercially available in the subject’s country, whichever occurred first. Apheresis treatment was not required in the open-label treatment period and could be stopped or continued at the investigator’s discretion.

    Primary: Rate of Apheresis Treatment From Week 7 to Week 18

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    End point title
    		 Rate of Apheresis Treatment From Week 7 to Week 18
    End point description
    The normalized rate of apheresis was defined for each subject as the number of actual apheresis treatments received from week 7 to week 18 divided by the number of planned apheresis treatments per randomization strata at baseline (6 for Q2W and 12 for QW). Intent-to-treat (ITT) population defined as all randomized subjects and were analyzed according to the treatment group allocated by randomization.
    End point type
    Primary
    End point timeframe
    Week 7 up to Week 18 (before the start of open-label treatment dose)
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Rate of treatment
        arithmetic mean (standard deviation)
    0.853 ± 0.184
    0.378 ± 0.376
    Statistical analysis title
    		 Alirocumab 150 mg Q2W vs Placebo Q2W
    Statistical analysis description
    Analysis was performed using the ranked analysis of covariance (ANCOVA) model with baseline frequency of the apheresis procedure (QW or Q2W) and Lipoprotein (a) (Lp [a]) levels (normal or elevated) as fixed effect and the baseline LDL-C level as a covariate. Median treatment difference and 95% confidence interval (CI) was derived from the Hodges-Lehmann (H-L) estimation and Moses distribution free CI, respectively.
    Comparison groups
    Alirocumab 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Ranked Median Difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.333
         upper limit
    		 0.75
    Notes
    [1] - Threshold for significance at 0.05 level.

    Secondary: Percent Change From Baseline in Calculated Low-density Lipoprotein Cholesterol (LDL-C) (Pre-Apheresis) to Week 6

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    End point title
    		 Percent Change From Baseline in Calculated Low-density Lipoprotein Cholesterol (LDL-C) (Pre-Apheresis) to Week 6
    End point description
    Adjusted Least-squares (LS) means and standard errors at Week 6 were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data. All available post-baseline data from Week 2 to Week 18 regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population that included all randomized subjects with baseline and at least one post-baseline pre-apheresis calculated LDL-C value up to week 6, analyzed according to the treatment group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 6
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    1.6 ± 3.1
    -53.6 ± 2.3
    Statistical analysis title
    		 Alirocumab 150 mg Q2W vs Placebo Q2W
    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 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 MMRM
    Parameter type
    		 Least Square (LS) mean difference
    Point estimate
    -55.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -63
         upper limit
    		 -47.5
    Notes
    [2] - Threshold for significance at 0.05 level.

    Secondary: Rate of Apheresis Treatment from Week 15 to Week 18

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    End point title
    		 Rate of Apheresis Treatment from Week 15 to Week 18
    End point description
    The normalized rate of apheresis was defined for each subject as the number of actual apheresis treatments received from week 15 to week 18 divided by the planned apheresis treatments per randomization strata at baseline (2 for Q2W and 4 for QW). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 15 up to Week 18 (before the start of open-label treatment dose)
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Rate of treatment
        median (full range (min-max))
    1 (0 to 1)
    0.500 (0 to 1)
    Statistical analysis title
    		 Alirocumab 150 mg Q2W vs Placebo Q2W
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Alirocumab 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [3]
    Method
    		 ANCOVA
    Parameter type
    		 Ranked Median Difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.5
    Notes
    [3] - Threshold for significance at 0.05 level.

    Secondary: Percent Change From Baseline in Apolipoprotein B (Apo B) (Pre-apheresis) to Week 6

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B (Apo B) (Pre-apheresis) to Week 6
    End point description
    Adjusted LS means and standard errors at Week 6 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 6
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    1.2 ± 3
    -42.8 ± 2.1
    Statistical analysis title
    		 Alirocumab 150 mg Q2W vs Placebo Q2W
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Alirocumab 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.3
         upper limit
    		 -36.6
    Notes
    [4] - Threshold for significance at 0.05 level.

    Secondary: Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) (Pre-apheresis) to Week 6

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    End point title
    		 Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) (Pre-apheresis) to Week 6
    End point description
    Adjusted LS means and standard errors at Week 6 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 6
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    2.8 ± 2.9
    -47.1 ± 2.1
    Statistical analysis title
    		 Alirocumab 150 mg Q2W vs Placebo Q2W
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Alirocumab 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -50
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.3
         upper limit
    		 -42.7
    Notes
    [5] - Threshold for significance at 0.05 level.

    Secondary: Percent Change From Baseline in Total Cholesterol (Pre-apheresis) to Week 6

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    End point title
    		 Percent Change From Baseline in Total Cholesterol (Pre-apheresis) to Week 6
    End point description
    Adjusted LS means and standard errors at Week 6 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 6
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    3.1 ± 2.5
    -36.4 ± 1.8
    Statistical analysis title
    		 Alirocumab 150 mg Q2W vs Placebo Q2W
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Alirocumab 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -39.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -45.6
         upper limit
    		 -33.2
    Notes
    [6] - Threshold for significance at 0.05 level.

    Secondary: Percent Change From Baseline in Apolipoprotein A (Apo A1) (Pre-apheresis) to Week 6

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    End point title
    		 Percent Change From Baseline in Apolipoprotein A (Apo A1) (Pre-apheresis) to Week 6
    End point description
    Adjusted LS means and standard errors at Week 6 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 6
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    0 ± 3.3
    4.2 ± 2.4
    Statistical analysis title
    		 Alirocumab 150 mg Q2W vs Placebo Q2W
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Alirocumab 150 mg Q2W v Placebo Q2W
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3012 [7]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    4.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.9
         upper limit
    		 12.3
    Notes
    [7] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects with At least (>=) 30% Reduction in Calculated LDL-C (Pre-apheresis) at Week 6

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    End point title
    		 Percentage of Subjects with At least (>=) 30% Reduction in Calculated LDL-C (Pre-apheresis) at Week 6
    End point description
    Percentage of subjects at Week 6 was obtained from a last observation carried forward (LOCF) model for handling of missing data. All available post-baseline data regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 6
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percentage of subjects
        number (not applicable)
    4.8
    95.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with At least (>=) 50% Reduction in Calculated LDL-C (Pre-apheresis) at Week 6

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    End point title
    		 Percentage of Subjects with At least (>=) 50% Reduction in Calculated LDL-C (Pre-apheresis) at Week 6
    End point description
    Percentage of subjects at Week 6 was obtained from LOCF model for handling of missing data. All available post-baseline data regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 6
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percentage of subjects
        number (not applicable)
    0
    63.4
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Calculated LDL-C (Pre-Apheresis) to Week 18

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C (Pre-Apheresis) to Week 18
    End point description
    Adjusted LS means and standard errors at Week 18 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 18
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    4 ± 6.2
    -42.3 ± 4.5
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Apolipoprotein B (Apo B) (Pre-apheresis) to Week 18

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B (Apo B) (Pre-apheresis) to Week 18
    End point description
    Adjusted LS means and standard errors at Week 18 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 18
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    1.7 ± 4.8
    -33.8 ± 3.5
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Non-HDL-C (Pre-apheresis) to Week 18

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    End point title
    		 Percent Change From Baseline in Non-HDL-C (Pre-apheresis) to Week 18
    End point description
    Adjusted LS means and standard errors at Week 18 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 18
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    4.7 ± 5.6
    -35.7 ± 4.1
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Total Cholesterol (Pre-apheresis) to Week 18

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    End point title
    		 Percent Change From Baseline in Total Cholesterol (Pre-apheresis) to Week 18
    End point description
    Adjusted LS means and standard errors at Week 18 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 18
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    4.7 ± 4.7
    -27.1 ± 3.4
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Apo A1 (Pre-apheresis) to Week 18

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    End point title
    		 Percent Change From Baseline in Apo A1 (Pre-apheresis) to Week 18
    End point description
    Adjusted LS means and standard errors at Week 18 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 18
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    -0.7 ± 3.4
    7.8 ± 2.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with At least (>=) 30% Reduction in Calculated LDL-C (Pre-apheresis) at Week 18

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    End point title
    		 Percentage of Subjects with At least (>=) 30% Reduction in Calculated LDL-C (Pre-apheresis) at Week 18
    End point description
    Percentage of subjects at Week 18 was obtained from LOCF model for handling of missing data. All available post-baseline data regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 18
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percentage of subjects
        number (not applicable)
    0
    65.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with At least (>=) 50% Reduction in Calculated LDL-C (Pre-apheresis) at Week 18

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    End point title
    		 Percentage of Subjects with At least (>=) 50% Reduction in Calculated LDL-C (Pre-apheresis) at Week 18
    End point description
    Percentage of subjects at Week 18 was obtained from LOCF model for handling of missing data. All available post-baseline data regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 18
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percentage of subjects
        number (not applicable)
    0
    43.9
    No statistical analyses for this end point

    Secondary: Change From Baseline in W-BQ22 (Well-being Questionnaire) Index Score at Week 18

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    End point title
    		 Change From Baseline in W-BQ22 (Well-being Questionnaire) Index Score at Week 18
    End point description
    The W-BQ22 (well-being) questionnaire was a standardized and generic instrument used for measuring the impact of hypercholesterolemia and treatment on well-being of subjects. The general well-being score was calculated as the sum of 22 questions in the W-BQ22 questionnaire (each question scored from 0 to 3 [0 = not at all and 3 = all the time]). Total score for 22 questions range from 0 to 66 [0 = worst condition and 66 = best well-being condition). Analysis was performed on Well-Being analysis set included all randomized and treated subjects with complete baseline and complete post-baseline evaluations of the 22-question well-being questionnaire.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 18
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    19
    38
    Units: units on a score
        least squares mean (standard error)
    -1.43 ± 1.441
    0.91 ± 1.04
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Lipoprotein (a) (Lp [a]) (Pre-apheresis) to Week 6

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    End point title
    		 Percent Change From Baseline in Lipoprotein (a) (Lp [a]) (Pre-apheresis) to Week 6
    End point description
    Adjusted means and standard errors at Week 6 from a multiple imputation approach followed by robust regression model including all available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 6
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    -4 ± 5.1
    -18.1 ± 3.7
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) (Pre-apheresis) to Week 6

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    End point title
    		 Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) (Pre-apheresis) to Week 6
    End point description
    Adjusted LS means and standard errors at Week 6 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 6
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    4 ± 3.4
    9.3 ± 2.4
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Triglyceride (TG) levels (Pre-apheresis) to Week 6

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    End point title
    		 Percent Change From Baseline in Triglyceride (TG) levels (Pre-apheresis) to Week 6
    End point description
    Adjusted means and standard errors at Week 6 from a multiple imputation approach followed by robust regression model including all available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 6
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    3 ± 5.6
    -12.9 ± 4
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Lp (a) (Pre-apheresis) to Week 18

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    End point title
    		 Percent Change From Baseline in Lp (a) (Pre-apheresis) to Week 18
    End point description
    Adjusted means and standard errors at Week 18 from a multiple imputation approach followed by robust regression model including all available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 18
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    -1.2 ± 8
    -6.1 ± 5.9
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in HDL-C (Pre-apheresis) to Week 18

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    End point title
    		 Percent Change From Baseline in HDL-C (Pre-apheresis) to Week 18
    End point description
    Adjusted LS means and standard errors at Week 18 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 18
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    2.4 ± 5
    10.9 ± 3.6
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in TG Levels (Pre-apheresis) to Week 18

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    End point title
    		 Percent Change From Baseline in TG Levels (Pre-apheresis) to Week 18
    End point description
    Adjusted means and standard errors at Week 18 from a multiple imputation approach followed by robust regression model including all available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 18
    End point values
    		 Placebo Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    21
    41
    Units: Percent change
        least squares mean (standard error)
    4.1 ± 7.9
    -2.4 ± 5.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to the final study end visit (maximum duration: 46 weeks) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs are treatment-emergent AEs developed/worsened during ‘on treatment period’(double blind treatment-emergent period: time from first dose of study drug to last double-blind dose+70 days, prior to first open-label dose of study drug; open-label treatment emergent period: time from first open-label dose of study drug to last dose+70 days).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo Q2W (DB Period)
    Reporting group description
    		 Placebo (for alirocumab) subcutaneous (SC) injection Q2W up to Week 16 (mean exposure of 17 weeks).

    Reporting group title
    Alirocumab 150 mg Q2W (DB Period)
    Reporting group description
    		 Alirocumab 150 mg SC injection Q2W up to Week 16 (mean exposure of 17 weeks).

    Reporting group title
    Alirocumab 150 mg Q2W (OLE Period)
    Reporting group description
    		 Alirocumab 150 mg SC injection Q2W from Week 18 (mean exposure of 17 weeks).

    Serious adverse events
    		 Placebo Q2W (DB Period) Alirocumab 150 mg Q2W (DB Period) Alirocumab 150 mg Q2W (OLE Period)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 21 (9.52%)
    4 / 41 (9.76%)
    1 / 29 (3.45%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Muscle rupture
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 41 (2.44%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery restenosis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 41 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shunt thrombosis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 41 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 41 (4.88%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 41 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 41 (2.44%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 41 (2.44%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 41 (2.44%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 41 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 41 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 41 (2.44%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Compartment syndrome
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 41 (2.44%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 41 (2.44%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 41 (2.44%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Q2W (DB Period) Alirocumab 150 mg Q2W (DB Period) Alirocumab 150 mg Q2W (OLE Period)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 21 (47.62%)
    22 / 41 (53.66%)
    2 / 29 (6.90%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 41 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 41 (7.32%)
    0 / 29 (0.00%)
         occurrences all number
    2
    5
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 41 (2.44%)
    2 / 29 (6.90%)
         occurrences all number
    0
    1
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 21 (9.52%)
    6 / 41 (14.63%)
    0 / 29 (0.00%)
         occurrences all number
    2
    6
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 21 (0.00%)
    4 / 41 (9.76%)
    0 / 29 (0.00%)
         occurrences all number
    0
    4
    0
    Nausea
         subjects affected / exposed
    3 / 21 (14.29%)
    2 / 41 (4.88%)
    0 / 29 (0.00%)
         occurrences all number
    4
    4
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 41 (7.32%)
    0 / 29 (0.00%)
         occurrences all number
    2
    5
    0
    Back pain
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 41 (4.88%)
    0 / 29 (0.00%)
         occurrences all number
    4
    4
    0
    Myalgia
         subjects affected / exposed
    1 / 21 (4.76%)
    5 / 41 (12.20%)
    0 / 29 (0.00%)
         occurrences all number
    1
    5
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 21 (9.52%)
    4 / 41 (9.76%)
    1 / 29 (3.45%)
         occurrences all number
    2
    4
    2
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 21 (19.05%)
    3 / 41 (7.32%)
    0 / 29 (0.00%)
         occurrences all number
    4
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Apr 2015
    Following changes were made: - Allowed flexibility in apheresis treatment eligibility requirements; - Added an open-label treatment period; - Updated site locations; - made minor clarifications.
    06 Jul 2015
    Following changes were made: - Updated eligibility requirements that were consistent with the known safety profile of the study drug; - Made a minor clarification to the text regarding the apheresis schedule.
    22 Sep 2015
    Following changes were made: -Noted that entry into the open-label treatment period was only available to subjects who were study participants in a country in which alirocumab not commercially available (sites in Germany); -Indicated that treatment in the open-label period of the study would continue for a maximum of 76 weeks or until alirocumab was commercially available in the subject’s country, whichever comes first (sites in Germany); -Clarified that subjects who chose not to participate in the open-label treatment period, or who were study subjects in a country in which alirocumab was commercially available (sites in the US), would be seen at week 26 for the double-blind treatment period end of study visit. These subjects were considered to have completed the study at this end of study visit;- -Specified that the primary analysis would be performed following the completion of the double-blind treatment period and made minor administrative corrections/clarifications.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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