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    Clinical Trial Results:
    An Open-Label Study to Evaluate the Efficacy and Safety of Alirocumab in Children and Adolescents With Homozygous Familial Hypercholesterolemia

    Summary
    EudraCT number
    		 2017-002297-39
    Trial protocol
    		 NO   FR   NL   IT   DK   AT   SI   ES   BG   Outside EU/EEA  
    Global end of trial date
    17 Feb 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 Jan 2023
    First version publication date
    28 Aug 2020
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Updated safety optional field

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC14660
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03510715
    WHO universal trial number (UTN)
    		 U1111-1200-2046
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001169-PIP01-11
    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
    16 Mar 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of alirocumab (75 or 150 milligram [mg] depending on body weight [BW]), administered every 2 weeks (Q2W), on low-density lipoprotein cholesterol (LDL-C) levels at Week 12 of treatment in children with homozygous familial hypercholesterolemia (hoFH) of 8 to 17 years of age on top of background treatments.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of paediatric subjects. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimised. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimise distress and discomfort.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Aug 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
    Netherlands: 2
    Country: Number of subjects enrolled
    Slovenia: 2
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    Brazil: 1
    Worldwide total number of subjects
    18
    EEA total number of subjects
    8
    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)
    8
    Adolescents (12-17 years)
    10
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 10 active centres (which screened at least 1 subject) in 10 countries worldwide. Overall 20 subjects were screened between 31 August 2018 and 4 January 2019, of whom 2 were screen failures. Of the 10 centers which screened subjects, 9 centers enrolled at least 1 subject.

    Pre-assignment
    Screening details
    		 A total of 18 subjects were enrolled and received treatment in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Alirocumab 75 mg Q2W/up to 150 mg Q2W
    Arm description
    		 Subjects with BW less than (<) 50 kilograms (kg) received subcutaneous (SC) injection of alirocumab 75 mg Q2W for 48 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 in case of increase in BW with BW greater than or equal to [>=] 50 kg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    SAR236553
    Other name
    Praluent
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 75 mg alirocumab Q2W for 48 weeks. After Week 12, dose was up-titrated to 150 mg Q2W in case of change in BW with BW >=50 kg.

    Arm title
    		 Alirocumab 150 mg Q2W
    Arm description
    		 Subjects with BW >=50 kg received SC injection of alirocumab 150 mg Q2W for 48 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    SAR236553
    Other name
    Praluent
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 150 mg alirocumab Q2W for 48 weeks.

    Number of subjects in period 1
    		Alirocumab 75 mg Q2W/up to 150 mg Q2W Alirocumab 150 mg Q2W
    Started
    9
    9
    Completed
    8
    9
    Not completed
    1
    0
         Adverse event
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alirocumab 75 mg Q2W/up to 150 mg Q2W
    Reporting group description
    		 Subjects with BW less than (<) 50 kilograms (kg) received subcutaneous (SC) injection of alirocumab 75 mg Q2W for 48 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 in case of increase in BW with BW greater than or equal to [>=] 50 kg.

    Reporting group title
    Alirocumab 150 mg Q2W
    Reporting group description
    		 Subjects with BW >=50 kg received SC injection of alirocumab 150 mg Q2W for 48 weeks.

    Reporting group values
    		 Alirocumab 75 mg Q2W/up to 150 mg Q2W Alirocumab 150 mg Q2W Total
    Number of subjects
    		 9 9 18
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.4 ± 1.5 14.3 ± 2.4 -
    Gender categorical
    Units: Subjects
        Female
    		 4 5 9
        Male
    		 5 4 9
    Race
    Units: Subjects
        White
    		 6 5 11
        Black or African American
    		 0 1 1
        Asian
    		 1 2 3
        American Indian or Alaska Native
    		 2 1 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
    Low-Density Lipoprotein Cholesterol (LDL-C)
    Units: milligrams per decilitre (mg/dL)
        arithmetic mean (standard deviation)
    		 437.7 ± 192.8 308.3 ± 181.6 -

    End points

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    End points reporting groups
    Reporting group title
    Alirocumab 75 mg Q2W/up to 150 mg Q2W
    Reporting group description
    		 Subjects with BW less than (<) 50 kilograms (kg) received subcutaneous (SC) injection of alirocumab 75 mg Q2W for 48 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 in case of increase in BW with BW greater than or equal to [>=] 50 kg.

    Reporting group title
    Alirocumab 150 mg Q2W
    Reporting group description
    		 Subjects with BW >=50 kg received SC injection of alirocumab 150 mg Q2W for 48 weeks.

    Subject analysis set title
    Alirocumab
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who received either 75 mg (BW <50 kg) or 150 mg (BW >=50 kg) alirocumab subcutaneously Q2W for 48 weeks.

    Primary: Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12: Intent-to-Treat (ITT) Analysis

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    End point title
    		 Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12: Intent-to-Treat (ITT) Analysis [1]
    End point description
    Adjusted least square (LS) means and standard errors were obtained from the mixed model analysis with repeated measures (MMRM) to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). As pre-specified, efficacy analysis data were planned to be collected and analysed for all doses combined (i.e. for combined population). Analysis was performed on ITT population which included all enrolled subjects who received at least one dose or partial dose of alirocumab.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported.
    End point values
    		 Alirocumab
    Number of subjects analysed
    18
    Units: Percent change
        least squares mean (standard error)
    -4.1 ± 9.0
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Low-Density Lipoprotein Cholesterol at Week 12: On-treatment Analysis

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    End point title
    		 Percent Change From Baseline in Low-Density Lipoprotein Cholesterol at Week 12: On-treatment Analysis
    End point description
    Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline on-treatment data from Week 4 to Week 48 (on-treatment analysis). As pre-specified, efficacy analysis data were planned to be collected and analysed for all doses combined (i.e. for combined population). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Alirocumab
    Number of subjects analysed
    18
    Units: Percent Change
        least squares mean (standard error)
    -4.1 ± 9.0
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Low-Density Lipoprotein Cholesterol at Weeks 24 and 48: ITT Analysis/On-treatment Analysis

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    End point title
    		 Percent Change From Baseline in Low-Density Lipoprotein Cholesterol at Weeks 24 and 48: ITT Analysis/On-treatment Analysis
    End point description
    Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, the results would be identical and a single endpoint presenting the results for both types of analysis would be provided. As pre-specified, efficacy analysis data were planned to be collected and analysed for all doses combined (i.e. for combined population). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 24 and 48
    End point values
    		 Alirocumab
    Number of subjects analysed
    18
    Units: Percent Change
    least squares mean (standard error)
        Week 24
    -10.1 ± 7.6
        Week 48
    4.2 ± 12.8
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Apolipoprotein (Apo) B at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis

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    End point title
    		 Percent Change From Baseline in Apolipoprotein (Apo) B at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
    End point description
    Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, the results would be identical and a single endpoint presenting the results for both types of analysis would be provided. As pre-specified, efficacy analysis data were planned to be collected and analysed for all doses combined (i.e. for combined population). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 12, 24 and 48
    End point values
    		 Alirocumab
    Number of subjects analysed
    18
    Units: Percent Change
    least squares mean (standard error)
        Week 12
    -4.2 ± 6.8
        Week 24
    -11.8 ± 6.1
        Week 48
    0.9 ± 10.4
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Weeks 12, 24 and 48 - ITT Analysis/On-treatment Analysis

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    End point title
    		 Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Weeks 12, 24 and 48 - ITT Analysis/On-treatment Analysis
    End point description
    Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, the results would be identical and a single endpoint presenting the results for both types of analysis would be provided. As pre-specified, efficacy analysis data were planned to be collected and analysed for all doses combined (i.e. for combined population). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 12, 24 and 48
    End point values
    		 Alirocumab
    Number of subjects analysed
    18
    Units: Percent Change
    least squares mean (standard error)
        Week 12
    -3.9 ± 8.3
        Week 24
    -9.2 ± 7.3
        Week 48
    5.7 ± 13.1
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Total Cholesterol (Total-C) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis

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    End point title
    		 Percent Change From Baseline in Total Cholesterol (Total-C) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
    End point description
    Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Weeks 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, the results would be identical and a single endpoint presenting the results for both types of analysis would be provided. As pre-specified, efficacy analysis data were planned to be collected and analysed for all doses combined (i.e. for combined population). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 12, 24 and 48
    End point values
    		 Alirocumab
    Number of subjects analysed
    18
    Units: Percent Change
    least squares mean (standard error)
        Week 12
    -1.9 ± 7.2
        Week 24
    -6.3 ± 6.5
        Week 48
    5.5 ± 10.7
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Lipoprotein a (Lp) (a) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis

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    End point title
    		 Percent Change From Baseline in Lipoprotein a (Lp) (a) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
    End point description
    Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data from Week 4 to Week 48 regardless of status on-or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, the results would be identical and a single endpoint presenting the results for both types of analysis would be provided. As pre-specified, efficacy analysis data were planned to be collected and analysed for all doses combined (i.e. for combined population). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 12, 24 and 48
    End point values
    		 Alirocumab
    Number of subjects analysed
    18
    Units: Percent Change
    arithmetic mean (standard error)
        Week 12
    7.4 ± 7.6
        Week 24
    -5.2 ± 8.1
        Week 48
    -6.4 ± 12.2
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis

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    End point title
    		 Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
    End point description
    Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Weeks 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, the results would be identical and a single endpoint presenting the results for both types of analysis would be provided. As pre-specified, efficacy analysis data were planned to be collected and analysed for all doses combined (i.e. for combined population). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 12, 24 and 48
    End point values
    		 Alirocumab
    Number of subjects analysed
    18
    Units: Percent Change
    least squares mean (standard error)
        Week 12
    13.0 ± 5.9
        Week 24
    8.9 ± 4.4
        Week 48
    10.1 ± 5.5
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Fasting Triglycerides (TG) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis

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    End point title
    		 Percent Change From Baseline in Fasting Triglycerides (TG) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
    End point description
    Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data from Week 4 to Week 48 regardless of status on-or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, the results would be identical and a single endpoint presenting the results for both types of analysis would be provided. As pre-specified, efficacy analysis data were planned to be collected and analysed for all doses combined (i.e. for combined population). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 12, 24 and 48
    End point values
    		 Alirocumab
    Number of subjects analysed
    18
    Units: Percent Change
    arithmetic mean (standard error)
        Week 12
    2.8 ± 8.0
        Week 24
    5.2 ± 16.2
        Week 48
    10.0 ± 8.2
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Apolipoprotein A1 (Apo A1) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis

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    End point title
    		 Percent Change From Baseline in Apolipoprotein A1 (Apo A1) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
    End point description
    Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, the results would be identical and a single endpoint presenting the results for both types of analysis would be provided. As pre-specified, efficacy analysis data was planned to be collected and analysed for all doses combined (i.e. for combined population). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 12, 24 and 48
    End point values
    		 Alirocumab
    Number of subjects analysed
    18
    Units: Percent Change
    least squares mean (standard error)
        Week 12
    11.3 ± 6.9
        Week 24
    14.6 ± 6.0
        Week 48
    11.3 ± 5.8
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting >=15 Percent (%) Reduction in LDL-C Level at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis

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    End point title
    		 Percentage of Subjects Reporting >=15 Percent (%) Reduction in LDL-C Level at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
    End point description
    Adjusted Percentage were obtained from a multiple imputation approach for handling of missing data including all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, the results would be identical and a single endpoint presenting the results for both types of analysis would be provided. As pre-specified, efficacy analysis data were planned to be collected and analysed for all doses combined (i.e. for combined population). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Weeks 12, 24 and 48
    End point values
    		 Alirocumab
    Number of subjects analysed
    18
    Units: Percentage of subjects
    number (confidence interval 95%)
        Week 12
    50.0 (26.2 to 73.8)
        Week 24
    50.0 (26.2 to 73.8)
        Week 48
    39.0 (15.8 to 62.2)
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in LDL-C Level at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis

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    End point title
    		 Absolute Change From Baseline in LDL-C Level at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
    End point description
    Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, the results would be identical and a single endpoint presenting the results for both types of analysis would be provided. As pre-specified, efficacy analysis data were planned to be collected and analysed for all doses combined (i.e. for combined population). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 12, 24 and 48
    End point values
    		 Alirocumab
    Number of subjects analysed
    18
    Units: mg/dL
    least squares mean (standard error)
        Week 12
    -33.4 ± 19.1
        Week 24
    -43.0 ± 19.0
        Week 48
    -15.0 ± 25.7
    No statistical analyses for this end point

    Secondary: Number of Subjects With Tanner Staging at Weeks 12, 24 and 48

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    End point title
    		 Number of Subjects With Tanner Staging at Weeks 12, 24 and 48
    End point description
    Tanner stage defines physical measurements of development in children and adolescent based on external primary and secondary sex characteristics. Subjects were evaluated for pubic hair distribution, breast development (only females) and genital development (only males), and classified in 3 categories as: Prepubescent (defined as a person just before start of the development of adult sexual characteristics), Pubescent (defined as a person at or approaching the age of puberty), Postpubescent (sexually mature or a person who has completed puberty). Analysis was performed on safety population which included subjects who received at least one dose or partial dose of alirocumab. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24 and 48
    End point values
    		 Alirocumab 75 mg Q2W/up to 150 mg Q2W Alirocumab 150 mg Q2W
    Number of subjects analysed
    9
    9
    Units: Subjects
    number (not applicable)
        Baseline: Prepubescent (n = 9, 9)
    3
    0
        Baseline: Pubescent (n = 9, 9)
    6
    9
        Baseline: Post-pubescent (n = 9, 9)
    0
    0
        Week 12: Prepubescent (n = 9, 9)
    3
    0
        Week 12: Pubescent (n = 9, 9)
    6
    8
        Week 12: Post-pubescent (n=9, 9)
    0
    1
        Week 24: Prepubescent (n = 8, 9)
    2
    0
        Week 24: Pubescent (n = 8, 9)
    6
    8
        Week 24: Post-pubescent (n = 8, 9)
    0
    1
        Week 48: Prepubescent (n = 8, 9)
    1
    0
        Week 48: Pubescent (n = 8, 9)
    7
    7
        Week 48: Post-pubescent (n = 8, 9)
    0
    2
    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 56 weeks of the study regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs and death were treatment-emergent AEs (TEAE) that developed/worsened, and death that occurred during TEAE period (the time from the first dose of alirocumab up to the last dose of alirocumab + 70 days [10 weeks]). Analysis was performed on safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Alirocumab 150 mg Q2W
    Reporting group description
    		 Subjects with BW >=50 kg received SC injection of alirocumab 150 mg Q2W for 48 weeks.

    Reporting group title
    Alirocumab 75 mg Q2W/up to 150 mg Q2W
    Reporting group description
    		 Subjects with BW <50 kg received SC injection of alirocumab 75 mg Q2W for 48 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 in case of increase in BW with BW >=50 kg.

    Serious adverse events
    		 Alirocumab 150 mg Q2W Alirocumab 75 mg Q2W/up to 150 mg Q2W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Cardiac disorders
    Cardiac Failure
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Alirocumab 150 mg Q2W Alirocumab 75 mg Q2W/up to 150 mg Q2W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    8 / 9 (88.89%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Influenza Like Illness
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Injection Site Pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Injection Site Reaction
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
         occurrences all number
    1
    2
    Dyspnoea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea Paroxysmal Nocturnal
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Thermal Burn
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Congenital, familial and genetic disorders
    Bicuspid Aortic Valve
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Aortic Valve Incompetence
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 9 (22.22%)
         occurrences all number
    1
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 9 (22.22%)
         occurrences all number
    2
    4
    Blood and lymphatic system disorders
    Splenomegaly
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain In Extremity
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Tendon Pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Tendonitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 9 (11.11%)
         occurrences all number
    2
    1
    Parvovirus B19 Infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Urinary Tract Infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Feb 2018
    Following amendments were made: Addition of the interactive response technology (IRT) contact performed during Visit 3 (intermediate visit) of the screening period. In addition, several inconsistencies, typographical errors, and other grammatical errors were corrected as well.
    11 Sep 2018
    The amendment was done to specify that the optional consent for genotyping was part of the main informed consent form. To address the requests from the Norwegian and Argentinian regulatory agencies for monthly pregnancy tests on all female subjects of childbearing potential throughout the entire study.

    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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