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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Evinacumab in Patients with Homozygous Familial Hypercholesterolemia

    Summary
    EudraCT number
    		 2017-001388-19
    Trial protocol
    		 DE   FR   AT   CZ   GR   IT  
    Global end of trial date
    17 Mar 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    08 Jul 2021
    First version publication date
    03 Oct 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    R1500-CL-1629
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03399786
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Road, Tarrytown, NY, United States, 10591
    Public contact
    Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002298-PIP01-17
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Mar 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) using evinacumab 15 milligrams per kilogram (mg/kg) intravenously (IV) in comparison to placebo after 24 weeks in subjects with homozygous familial hypercholesterolemia (HoFH).
    Protection of trial subjects
    This study was conducted in accordance with the protocol and with the following: Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines; Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines; Applicable laws and regulations.
    Background therapy
    		 Study treatment was added on to the subjects’ stable background lipid modifying therapy. Subjects were on a maximally tolerated statin, ezetimibe, and a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor antibody unless the subject had a documented history of tolerability issues, little or no response to therapy, or other documented reason.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jan 2018
    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
    Australia: 4
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Japan: 10
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    South Africa: 8
    Country: Number of subjects enrolled
    Ukraine: 8
    Country: Number of subjects enrolled
    United States: 10
    Worldwide total number of subjects
    65
    EEA total number of subjects
    22
    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)
    2
    Adults (18-64 years)
    55
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 30 centers that enrolled subjects in 11 countries in Europe, Asia, North America, and Australia. Randomization was stratified by apheresis treatment status and by region (Japan, Rest of the World [ROW]).

    Pre-assignment
    Screening details
    		 A total of 75 subjects were screened and 65 subjects randomized. There were 10 subjects that were considered screen failures.

    Period 1
    Period 1 title
    Double-blind treatment period (DBTP)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    (day 1 to week 20)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo IV Q4W (DBTP)
    Arm description
    		 Subjects received IV infusion of placebo matched to evinacumab every 4 weeks (Q4W) from day 1 to week 20 in the double-blind treatment period (DBTP).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received IV infusion of placebo matched to evinacumab Q4W from day 1 to week 20

    Arm title
    		 Evinacumab 15 mg/kg IV Q4W (DBTP)
    Arm description
    		 Subjects received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from day 1 to week 20 in the double-blind treatment period (DBTP).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evinacumab
    Investigational medicinal product code
    REGN1500
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from day 1 to week 20

    Number of subjects in period 1
    		Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Started
    22
    43
    Completed
    21
    43
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -
    Period 2
    Period 2 title
    Open-label treatment period (OLTP)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo IV Q4W (OLTP)
    Arm description
    		 All subjects in the placebo arm who completed the double-blind treatment period (DBTP) received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from week 24 to week 44 in the open-label treatment period (OLTP).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evinacumab
    Investigational medicinal product code
    REGN1500
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from week 24 to week 44.

    Arm title
    		 Evinacumab 15 mg/kg IV Q4W (OLTP)
    Arm description
    		 All subjects who completed the double-blind treatment period (DBTP) received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from week 24 to week 44 in the open-label treatment period (OLTP).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evinacumab
    Investigational medicinal product code
    REGN1500
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from week 24 to week 44.

    Number of subjects in period 2
    		Placebo IV Q4W (OLTP) Evinacumab 15 mg/kg IV Q4W (OLTP)
    Started
    20
    44
    Completed
    19
    43
    Not completed
    1
    1
         Noncompliance with protocol by the subject
    1
    -
         Pregnancy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo IV Q4W (DBTP)
    Reporting group description
    		 Subjects received IV infusion of placebo matched to evinacumab every 4 weeks (Q4W) from day 1 to week 20 in the double-blind treatment period (DBTP).

    Reporting group title
    Evinacumab 15 mg/kg IV Q4W (DBTP)
    Reporting group description
    		 Subjects received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from day 1 to week 20 in the double-blind treatment period (DBTP).

    Reporting group values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP) Total
    Number of subjects
    		 22 43 65
    Age categorical
    Units: Subjects
        ≥12 to <18
    		 1 1 2
        ≥18 to <45
    		 16 23 39
        ≥45 to <65
    		 5 11 16
        ≥65 to <75
    		 0 7 7
        ≥75
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.7 ( 11.52 ) 44.3 ( 16.78 ) -
    Gender categorical
    Units: Subjects
        Male
    		 11 19 30
        Female
    		 11 24 35
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 1 2
        Not Hispanic or Latino
    		 20 38 58
        Not Reported
    		 1 4 5
    Race
    Units: Subjects
        White
    		 17 31 48
        Black or African American
    		 0 2 2
        Asian
    		 4 6 10
        American Indian or Alaska Native
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Not Reported
    		 0 2 2
        Other
    		 1 2 3
    Calculated Low-density Lipoprotein Cholesterol (LDL-C)
    Units: Milligrams per Deciliter (mg/dL)
        arithmetic mean (standard deviation)
    		 246.5 ( 153.71 ) 259.5 ( 172.40 ) -
    Apolipoprotein B (Apo B)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 175.9 ( 98.76 ) 169.1 ( 82.75 ) -
    Non-high-density Lipoprotein Cholesterol (non-HDL-C)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 269.9 ( 157.81 ) 281.9 ( 172.61 ) -
    Total Cholesterol (TC)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 315.9 ( 150.44 ) 325.6 ( 170.76 ) -
    Fasting Triglycerides (TG)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 144.1 ( 144.54 ) 113.1 ( 68.39 ) -
    Lipoprotein A (Lp[a])
    Units: Nanomoles per Liter (nmol/L)
        arithmetic mean (standard deviation)
    		 103.4 ( 109.43 ) 111.3 ( 114.40 ) -
    Apolipoprotein CIII (Apo CIII)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 9.7 ( 5.23 ) 9.2 ( 4.00 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo IV Q4W (DBTP)
    Reporting group description
    		 Subjects received IV infusion of placebo matched to evinacumab every 4 weeks (Q4W) from day 1 to week 20 in the double-blind treatment period (DBTP).

    Reporting group title
    Evinacumab 15 mg/kg IV Q4W (DBTP)
    Reporting group description
    		 Subjects received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from day 1 to week 20 in the double-blind treatment period (DBTP).
    Reporting group title
    Placebo IV Q4W (OLTP)
    Reporting group description
    		 All subjects in the placebo arm who completed the double-blind treatment period (DBTP) received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from week 24 to week 44 in the open-label treatment period (OLTP).

    Reporting group title
    Evinacumab 15 mg/kg IV Q4W (OLTP)
    Reporting group description
    		 All subjects who completed the double-blind treatment period (DBTP) received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from week 24 to week 44 in the open-label treatment period (OLTP).

    Primary: Percent Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) from Baseline to Week 24 (Intent-to-Treat [ITT] Estimand)

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    End point title
    		 Percent Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) from Baseline to Week 24 (Intent-to-Treat [ITT] Estimand)
    End point description
    Percent change was calculated as 100x(calculated LDL-C value at Week 24 - calculated LDL-C value at baseline)/calculated LDL-C value at baseline. The baseline LDL-C value was the last calculated LDL-C value obtained before the first dose of double-blind-study drug. The calculated LDL-C at week 24 was the LDL-C value obtained within the week 24 efficacy analysis window, regardless of adherence to treatment and subsequent therapies (intent-to-treat [ITT] estimand). The ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: Percent Change
        least squares mean (standard error)
    1.9 ( 6.5 )
    -47.1 ( 4.6 )
    Statistical analysis title
    		 Placebo IV Q4W, Evinacumab 15 mg/kg IV Q4W
    Statistical analysis description
    Confidence interval (CI) with p-value was based on-treatment group difference of least squares (LS) means using mixed-effect model repeat measurement (MMRM), randomization strata, treatment/strata/baseline value-by-time point interaction and continuous fixed covariates of baseline calculated LDL-C value.
    Comparison groups
    Placebo IV Q4W (DBTP) v Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed-effect Model Repeat Measure (MMRM)
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -65
         upper limit
    		 -33.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    8

    Secondary: Percent Change in Apolipoprotein B (Apo B) from Baseline to Week 24 (ITT Estimand)

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    End point title
    		 Percent Change in Apolipoprotein B (Apo B) from Baseline to Week 24 (ITT Estimand)
    End point description
    Percent change in Apo B from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: Percent Change
        least squares mean (standard error)
    -4.5 ( 4.8 )
    -41.4 ( 3.3 )
    Statistical analysis title
    		 Placebo IV Q4W, Evinacumab 15 mg/kg IV Q4W
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the secondary endpoints in a pre-specified order to control type I error. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. CI with p-value was based on-treatment group difference of LS means using MMRM, randomization strata, treatment/strata/baseline value-by-time point interaction and continuous fixed covariates of baseline calculated Apo B value.
    Comparison groups
    Placebo IV Q4W (DBTP) v Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed-effect Model Repeat Measure (MMRM)
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -36.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -48.6
         upper limit
    		 -25.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.9

    Secondary: Percent Change in Non-High-Density Lipoprotein Cholesterol (non-HDL-C) from Baseline to Week 24 (ITT Estimand)

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    End point title
    		 Percent Change in Non-High-Density Lipoprotein Cholesterol (non-HDL-C) from Baseline to Week 24 (ITT Estimand)
    End point description
    Percent change from baseline in non-HDL-C at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: Percent Change
        least squares mean (standard error)
    2.0 ( 5.4 )
    -49.7 ( 3.8 )
    Statistical analysis title
    		 Placebo IV Q4W, Evinacumab 15 mg/kg IV Q4W
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the secondary endpoints in a pre-specified order to control type I error. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. CI with p-value was based on-treatment group difference of LS means using MMRM, randomization strata, treatment/strata/baseline value-by-time point interaction and continuous fixed covariates of baseline calculated non-HDL-C value.
    Comparison groups
    Placebo IV Q4W (DBTP) v Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed-effect Model Repeat Measure (MMRM)
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -51.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -64.8
         upper limit
    		 -38.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.6

    Secondary: Percent Change in Total Cholesterol (TC) from Baseline to Week 24 (ITT Estimand)

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    End point title
    		 Percent Change in Total Cholesterol (TC) from Baseline to Week 24 (ITT Estimand)
    End point description
    Percent change in TC from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: Percent Change
        least squares mean (standard error)
    1.0 ( 4.2 )
    -47.4 ( 3.0 )
    Statistical analysis title
    		 Placebo IV Q4W, Evinacumab 15 mg/kg IV Q4W
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the secondary endpoints in a pre-specified order to control type I error. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. CI with p-value was based on-treatment group difference of LS means using MMRM, randomization strata, treatment/strata/baseline value-by-time point interaction and continuous fixed covariates of baseline calculated TC value.
    Comparison groups
    Placebo IV Q4W (DBTP) v Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed-effect Model Repeat Measure (MMRM)
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -48.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -58.7
         upper limit
    		 -38.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.1

    Secondary: Percentage of Subjects with ≥30% Reduction in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24 (ITT Estimand)

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    End point title
    		 Percentage of Subjects with ≥30% Reduction in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24 (ITT Estimand)
    End point description
    Percentage of subjects who achieved reduction in calculated LDL-C ≥30% at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: Percentage of Subjects
        number (not applicable)
    18.2
    83.7
    Statistical analysis title
    		 Placebo IV Q4W, Evinacumab 15 mg/kg IV Q4W
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for secondary endpoints in pre-specified order to control type I error.Testing sequence continued only when previous endpoint was statistically significant at 0.05.Multiple imputation addressed missing data at week 24.Combined estimate for odds ratio obtained by Rubin's formulae.Logistic regression models stratified by randomized strata include fixed categorical effect of treatment group & continuous fixed covariate of baseline calculated LDL-C.
    Comparison groups
    Placebo IV Q4W (DBTP) v Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 Logistic Regression Models Analyses
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    25.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.7
         upper limit
    		 110.5
    Notes
    [1] - A 2-step multiple imputation method addressed missing values (seeds = 1629 & 9261 with number of imputations = 100 in first and number of imputation=1 in second step).

    Secondary: Percentage of Subjects with ≥50% Reduction in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24 (ITT Estimand)

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    End point title
    		 Percentage of Subjects with ≥50% Reduction in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24 (ITT Estimand)
    End point description
    Percentage of subjects who achieved reduction in calculated LDL-C ≥ 50% at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: Percentage of Subjects
        number (not applicable)
    4.5
    55.8
    Statistical analysis title
    		 Placebo IV Q4W, Evinacumab 15 mg/kg IV Q4W
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for secondary endpoints in pre-specified order to control type I error.Testing sequence continued only when previous endpoint was statistically significant at 0.05.Multiple imputation addressed missing data at week 24.Combined estimate for odds ratio obtained by Rubin's formulae.Logistic regression models stratified by randomized strata include fixed categorical effect of treatment group & continuous fixed covariate of baseline calculated LDL-C.
    Comparison groups
    Placebo IV Q4W (DBTP) v Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0028
    Method
    		 Logistic Regression Models Analyses
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    24.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3
         upper limit
    		 195.6
    Notes
    [2] - A 2-step multiple imputation method addressed missing values (seeds = 1629 & 9261 with number of imputations = 100 in first and number of imputation=1 in second step).

    Secondary: Absolute Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) from Baseline to Week 24 (ITT Estimand)

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    End point title
    		 Absolute Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) from Baseline to Week 24 (ITT Estimand)
    End point description
    Absolute change in calculated LDL-C from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: Milligrams per Deciliter (mg/dL)
        least squares mean (standard error)
    -2.6 ( 17.6 )
    -134.7 ( 12.4 )
    Statistical analysis title
    		 Placebo IV Q4W, Evinacumab 15 mg/kg IV Q4W
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the secondary endpoints in a pre-specified order to control type I error. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. CI with p-value was based on-treatment group difference of LS means using MMRM, randomization strata, treatment/strata/baseline value-by-time point interaction and continuous fixed covariates of baseline calculated LDL-C value.
    Comparison groups
    Placebo IV Q4W (DBTP) v Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed-effect Model Repeat Measure (MMRM)
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -132.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -175.3
         upper limit
    		 -88.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    21.5

    Secondary: Percentage of Subjects Who Met United States (US) Apheresis Eligibility Criteria at Week 24 (ITT Estimand)

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    End point title
    		 Percentage of Subjects Who Met United States (US) Apheresis Eligibility Criteria at Week 24 (ITT Estimand)
    End point description
    US apheresis eligibility criteria included subjects who had inadequate response to diet and LMTs after 6 months of treatment and with Functional Homozygous familial hypercholesterolemia (HoFH) or Heterozygous familial hypercholesterolemia (HeFH) (with 0-1 risk factor) with LDL-C ≥ 300 mg/dL (7.77 mmol/L). Percentage of subjects who met US apheresis eligibility criteria at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: Percentage of Subjects
        number (not applicable)
    22.7
    7.0
    Statistical analysis title
    		 Placebo IV Q4W, Evinacumab 15 mg/kg IV Q4W
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the secondary endpoints in a pre-specified order to control type I error. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. Combined estimate for odds ratio was obtained by using Rubin's formulae. Logistic regression models stratified the fixed categorical effect of treatment group and the continuous fixed covariate of baseline calculated LDL-C value.
    Comparison groups
    Evinacumab 15 mg/kg IV Q4W (DBTP) v Placebo IV Q4W (DBTP)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0845
    Method
    		 Logistic Regression Models Analyses
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 1.3
    Notes
    [3] - A 2-step multiple imputation method addressed missing values (seeds = 1629 & 9261 with number of imputations = 100 in first and number of imputation=1 in second step).

    Secondary: Percentage of Subjects with Low-Density Lipoprotein Cholesterol (LDL-C) <100 milligrams per deciliter (mg/dL) (2.59 millimoles per liter [mmol/L]) at Week 24 (ITT Estimand)

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    End point title
    		 Percentage of Subjects with Low-Density Lipoprotein Cholesterol (LDL-C) <100 milligrams per deciliter (mg/dL) (2.59 millimoles per liter [mmol/L]) at Week 24 (ITT Estimand)
    End point description
    Percentage of subjects with LDL-C value <100 mg/dL (2.59 mmol/L) in the DBTP at Week 24 was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analysed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: Percentage of Subjects
        number (not applicable)
    22.7
    46.5
    Statistical analysis title
    		 Placebo IV Q4W, Evinacumab 15 mg/kg IV Q4W
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the secondary endpoints in a pre-specified order to control type I error. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. Combined estimate for odds ratio was obtained by using Rubin's formulae. Logistic regression models stratified the fixed categorical effect of treatment group and the continuous fixed covariate of baseline calculated LDL-C value.
    Comparison groups
    Evinacumab 15 mg/kg IV Q4W (DBTP) v Placebo IV Q4W (DBTP)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.0203 [5]
    Method
    		 Logistic Regression Models Analyses
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.3
         upper limit
    		 24.9
    Notes
    [4] - A 2-step multiple imputation method addressed missing values (seeds = 1629 & 9261 with number of imputations = 100 in first and number of imputation=1 in second step).
    [5] - The p-value is nominal for descriptive purpose only due to statistical hypothesis testing terminated previously.

    Secondary: Percentage of Subjects Who Met European Union (EU) Apheresis Eligibility Criteria at Week 24 (ITT Estimand)

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    End point title
    		 Percentage of Subjects Who Met European Union (EU) Apheresis Eligibility Criteria at Week 24 (ITT Estimand)
    End point description
    EU apheresis eligibility criteria included subjects who had inadequate response to diet and Lipid modifying therapies (LMTs) after 3 months of treatment, Primary prevention: Subjects with Familial hypercholesterolemia (FH) with LDL-C >160 mg/dL (4.2 mmol/L) and Cardiovascular (CV) events in close relatives. Secondary prevention: Subjects with progressive CV events with LDL-C > 120 to 130 mg/dL (3.1-3.4 mmol/L). Percentage of subjects who met EU apheresis eligibility criteria at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: Percentage of Subjects
        number (not applicable)
    77.3
    32.6
    Statistical analysis title
    		 Placebo IV Q4W, Evinacumab 15 mg/kg IV Q4W
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the secondary endpoints in a pre-specified order to control type I error. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. Combined estimate for odds ratio was obtained by using Rubin's formulae. Logistic regression models stratified the fixed categorical effect of treatment group and the continuous fixed covariate of baseline calculated LDL-C value.
    Comparison groups
    Placebo IV Q4W (DBTP) v Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.0004 [7]
    Method
    		 Logistic Regression Models Analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.3
    Notes
    [6] - A 2-step multiple imputation method addressed missing values (seeds = 1629 & 9261 with number of imputations = 100 in first and number of imputation=1 in second step).
    [7] - The p-value is nominal for descriptive purpose only due to statistical hypothesis testing terminated previously.

    Secondary: Percentage of Subjects with Calculated Low-Density Lipoprotein Cholesterol (LDL-C) <70 mg/dL (1.81 mmol/L) at Week 24 (ITT Estimand)

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    End point title
    		 Percentage of Subjects with Calculated Low-Density Lipoprotein Cholesterol (LDL-C) <70 mg/dL (1.81 mmol/L) at Week 24 (ITT Estimand)
    End point description
    Percentage of subjects with LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: Percentage of Subjects
        number (not applicable)
    4.5
    27.9
    No statistical analyses for this end point

    Secondary: Percent Change in Fasting Triglycerides (TG) from Baseline to Week 24 (ITT Estimand)

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    End point title
    		 Percent Change in Fasting Triglycerides (TG) from Baseline to Week 24 (ITT Estimand)
    End point description
    Percent change from baseline in TG at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: Percent Change
        least squares mean (standard error)
    -4.6 ( 7.0 )
    -55.0 ( 3.1 )
    No statistical analyses for this end point

    Secondary: Percent Change in Lipoprotein A (Lp[a]) from Baseline to Week 24 (ITT Estimand)

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    End point title
    		 Percent Change in Lipoprotein A (Lp[a]) from Baseline to Week 24 (ITT Estimand)
    End point description
    Percent change in Lp(a) from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: Percent Change
        least squares mean (standard error)
    -3.6 ( 5.8 )
    -5.5 ( 4.0 )
    No statistical analyses for this end point

    Secondary: Absolute Change in Apolipoprotein B (Apo B) from Baseline to Week 24 (ITT Estimand)

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    End point title
    		 Absolute Change in Apolipoprotein B (Apo B) from Baseline to Week 24 (ITT Estimand)
    End point description
    Absolute change in Apo B from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: mg/dL
        least squares mean (standard error)
    -8.0 ( 9.1 )
    -74.4 ( 6.3 )
    No statistical analyses for this end point

    Secondary: Absolute Change in Non-High-Density Lipoprotein Cholesterol (non-HDL-C) from Baseline to Week 24 (ITT Estimand)

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    End point title
    		 Absolute Change in Non-High-Density Lipoprotein Cholesterol (non-HDL-C) from Baseline to Week 24 (ITT Estimand)
    End point description
    Absolute change in non-HDL-C from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: mg/dL
        least squares mean (standard error)
    -0.4 ( 17.4 )
    -148.0 ( 12.3 )
    No statistical analyses for this end point

    Secondary: Absolute Change in Total Cholesterol (TC) from Baseline to Week 24 (ITT Estimand)

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    End point title
    		 Absolute Change in Total Cholesterol (TC) from Baseline to Week 24 (ITT Estimand)
    End point description
    Absolute change in TC from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: mg/dL
        least squares mean (standard error)
    -0.4 ( 17.2 )
    -161.6 ( 12.2 )
    No statistical analyses for this end point

    Secondary: Percent Change in Apolipoprotein CIII (Apo CIII) from Baseline to Week 24 (ITT Estimand)

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    End point title
    		 Percent Change in Apolipoprotein CIII (Apo CIII) from Baseline to Week 24 (ITT Estimand)
    End point description
    Percent change in Apo CIII from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized subjects who received at least one dose or part of a dose of double-blind study drug. Subjects in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized subject group).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg/kg IV Q4W (DBTP)
    Number of subjects analysed
    22
    43
    Units: Percent Change
        least squares mean (standard error)
    5.8 ( 5.5 )
    -84.1 ( 3.9 )
    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 until end of study (Week 68) regardless of seriousness or relationship to investigational product (IP).
    Adverse event reporting additional description
    For purpose of safety analysis, arm assignments for participants in Safety Set were based on actual treatment received, such that 1 participant assigned to Placebo arm who inadvertently received evinacumab 15mg/kg was included in Evinacumab 15mg/kg arm.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Placebo IV Q4W (DBTP)
    Reporting group description
    		 Subjects received IV infusion of placebo matched to evinacumab every 4 weeks (Q4W) from day 1 to week 20 in the double-blind treatment period (DBTP).

    Reporting group title
    Evinacumab 15 mg (DBTP)
    Reporting group description
    		 Subjects received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from day 1 to week 20 in the double-blind treatment period (DBTP).

    Reporting group title
    Placebo IV Q4W (OLTP)
    Reporting group description
    		 All subjects in the placebo arm who completed the double-blind treatment period (DBTP) received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from week 24 to week 44 in the open-label treatment period (OLTP).

    Reporting group title
    Evinacumab 15 mg (OLTP)
    Reporting group description
    		 All subjects in the evinacumab arm who completed the double-blind treatment period (DBTP) received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from week 24 to week 44 in the open-label treatment period (OLTP).

    Serious adverse events
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg (DBTP) Placebo IV Q4W (OLTP) Evinacumab 15 mg (OLTP)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 44 (4.55%)
    0 / 20 (0.00%)
    7 / 44 (15.91%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Cardiac procedure complication
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    0 / 20 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid artery restenosis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    0 / 20 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    0 / 20 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    0 / 20 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    0 / 20 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    0 / 20 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    0 / 20 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    0 / 20 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    0 / 20 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 44 (2.27%)
    0 / 20 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrocalcinosis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    0 / 20 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urosepsis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 44 (2.27%)
    0 / 20 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    0 / 20 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo IV Q4W (DBTP) Evinacumab 15 mg (DBTP) Placebo IV Q4W (OLTP) Evinacumab 15 mg (OLTP)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 21 (61.90%)
    20 / 44 (45.45%)
    12 / 20 (60.00%)
    19 / 44 (43.18%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 44 (0.00%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    1
    0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    0 / 21 (0.00%)
    5 / 44 (11.36%)
    0 / 20 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    0
    5
    0
    2
    Reproductive system and breast disorders
    Menstrual discomfort
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 44 (6.82%)
    0 / 20 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Asthma
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 44 (2.27%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Psychiatric disorders
    Generalised anxiety disorder
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 44 (0.00%)
    0 / 20 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Bacterial test positive
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Serum ferritin decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Procedural headache
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vaccination complication
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 21 (23.81%)
    4 / 44 (9.09%)
    1 / 20 (5.00%)
    5 / 44 (11.36%)
         occurrences all number
    6
    7
    2
    5
    Gastrointestinal disorders
    Toothache
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 44 (4.55%)
    1 / 20 (5.00%)
    1 / 44 (2.27%)
         occurrences all number
    2
    8
    1
    1
    Nausea
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 44 (2.27%)
    0 / 20 (0.00%)
    3 / 44 (6.82%)
         occurrences all number
    1
    1
    0
    4
    Constipation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 44 (2.27%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Urticaria
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 44 (2.27%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 44 (0.00%)
    0 / 20 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 44 (2.27%)
    0 / 20 (0.00%)
    3 / 44 (6.82%)
         occurrences all number
    0
    1
    0
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 21 (23.81%)
    7 / 44 (15.91%)
    1 / 20 (5.00%)
    5 / 44 (11.36%)
         occurrences all number
    6
    7
    2
    5
    Urinary tract infection
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 44 (0.00%)
    0 / 20 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    3
    0
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 44 (2.27%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Influenza
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 44 (0.00%)
    1 / 20 (5.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Dec 2017
    1. Added EuroQol-5D (EQ-5D) and Hospital Anxiety and Depression Scale (HADS) Quality of Life (QOL) questionnaires and an EQ-5D and HADS objective and exploratory endpoint to allow assessment of quality of life in this population. 2. Added Lipid Panel and Specialty Lipid Panel assessments and assessments of hematology, blood chemistry, and creatinine phosphokinase for the follow-up period. 3. Added a criterion excluding patients with LDL-C level <70 mg/dL as that was the goal for FH subjects. 4. Updated anti-drug antibody (ADA) variables and added a statement for follow-up of subjects positive in the ADA assay. 5. Added ADA sample at week 4. 6. Modified timing of one assessment for weight and one assessment for Pharmacokinetics (PK).
    21 Jun 2018
    1. Expanded Risk/Benefit section to include risk/benefit assessment of the combination of Evinacumab and Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, including alirocumab for the treatment of subjects with homozygous familial hypercholesterolemia (HoFH). 2. Clarified that subjects enrolling from R727-CL-1628 (2017-000351-95) will continue to receive alirocumab 150 mg every 2 weeks (Q2W).

    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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