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

    Summary
    EudraCT number
    		 2017-000351-95
    Trial protocol
    		 FR   AT   GR   IT  
    Global end of trial date
    13 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Feb 2021
    First version publication date
    26 Feb 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    R727-CL-1628
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03156621
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Rd., 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)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Feb 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) with alirocumab subcutaneous (SC) every 2 weeks (Q2W) in comparison to placebo after 12 weeks of treatment. The secondary objectives of the study were: To evaluate the effect of alirocumab Q2W on other lipid parameters (ie, apolipoprotein [Apo] A-1 and B, non-high-density lipoprotein cholesterol [non-HDL-C], total-cholesterol [TC], proportion of subjects with 15%, 30%, and 50% LDL-C reductions, Lp(a), HDL-C, triglycerides [TG]) in subjects with HoFH To evaluate the safety and tolerability of alirocumab SC Q2W in subjects with HoFH To assess the pharmacokinetics of alirocumab SC Q2W in subjects with HoFH To assess the potential development of anti-drug (alirocumab) antibodies (ADA)
    Protection of trial subjects
    This clinical study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with the International Council for Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Oct 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Japan: 8
    Country: Number of subjects enrolled
    South Africa: 6
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    Ukraine: 10
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    69
    EEA total number of subjects
    25
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    61
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited from 27 centers in 13 countries around Europe, Asia, South Africa, and North America. A total of 85 subjects were screened. Of those,16 were considered screen failures (mainly due to violations of inclusion/exclusion criteria).

    Pre-assignment
    Screening details
    		 Sixty-nine of the 85 subjects were eligible and randomized in a 2:1 ratio to receive either alirocumab 150 mg SC Q2W or matching placebo. Randomization was stratified by apheresis treatment status (Yes/No).

    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
    		 Investigator, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo in DBTP
    Arm description
    		 Subjects received matching placebo subcutaneously (SC) every 2 weeks (Q2W) from baseline (Day 1) through Week 10 during the double-blind treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo SC Q2W

    Arm title
    		 Alirocumab 150 mg SC Q2W in DBTP
    Arm description
    		 Subjects in this arm received alirocumab 150 milligrams (mg) SC Q2W from baseline (Day 1) through Week 10 during the double-blind treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    Other name
    PRALUENT® REGN727 SAR236553
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Alirocumab SC Q2W

    Number of subjects in period 1
    		Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Started
    24
    45
    Completed
    24
    45
    Period 2
    Period 2 title
    Open-Label Treatment Period (OLTP)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo in DBTP
    Arm description
    		 Subjects received matching placebo subcutaneously (SC) every 2 weeks (Q2W) from baseline (Day 1) through Week 10 during the double-blind treatment period. Starting at Week 12, and continuing through Week 22, all subjects received open-label alirocumab SC Q2W
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo SC Q2W **Not administered in OLTP, only administered in DBTP

    Arm title
    		 Alirocumab 150 mg SC Q2W
    Arm description
    		 Subjects in this arm received alirocumab 150 milligrams (mg) SC Q2W from baseline (Day 1) through Week 10 during the double-blind treatment period. Starting at Week 12, and continuing through Week 22, all subjects received open-label alirocumab SC Q2W
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    Other name
    PRALUENT® REGN727 SAR236553
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    150 mg SC Q2W

    Number of subjects in period 2
    		Placebo in DBTP Alirocumab 150 mg SC Q2W
    Started
    24
    45
    Completed
    24
    42
    Not completed
    0
    3
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo in DBTP
    Reporting group description
    		 Subjects received matching placebo subcutaneously (SC) every 2 weeks (Q2W) from baseline (Day 1) through Week 10 during the double-blind treatment period.

    Reporting group title
    Alirocumab 150 mg SC Q2W in DBTP
    Reporting group description
    		 Subjects in this arm received alirocumab 150 milligrams (mg) SC Q2W from baseline (Day 1) through Week 10 during the double-blind treatment period.

    Reporting group values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP Total
    Number of subjects
    		 24 45 69
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 20 41 61
        From 65-84 years
    		 4 4 8
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 45.4 ( 15.80 ) 42.3 ( 14.13 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 11 24 35
        Male
    		 13 21 34
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 18 36 54
        Black or African American
    		 0 2 2
        Asian
    		 5 7 12
        American Indian or Alaska Native
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Other
    		 1 0 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 2 2
        Not Hispanic or Latino
    		 24 43 67
        Unknown or Not Reported
    		 0 0 0
    Low-density lipoprotein cholesterol (LDL-C)
    Units: milligram/deciLiter (mg/dL)
        arithmetic mean (standard deviation)
    		 259.6 ( 175.75 ) 295.0 ( 154.59 ) -
    Non-high-density lipoprotein cholesterol (Non-HDL-C)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 282.0 ( 177.41 ) 320.5 ( 160.36 ) -
    Total-cholesterol (Total-C)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 325.1 ( 171.57 ) 364.3 ( 157.30 ) -
    High-density lipoprotein cholesterol (HDL-C)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 43.2 ( 11.96 ) 43.8 ( 14.78 ) -
    Fasting triglycerides (TG)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 111.7 ( 77.97 ) 128.0 ( 74.34 ) -
    Lipoprotein(a) [Lp(a)]
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 40.0 ( 36.41 ) 42.9 ( 36.34 ) -
    Apolipoprotein-B (Apo-B)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 175.0 ( 95.12 ) 193.3 ( 87.59 ) -
    Apolipoprotein-A1 (Apo-A1)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 124.8 ( 24.59 ) 125.6 ( 28.57 ) -
    Apo-B/Apo-A1
    Units: ratio
        arithmetic mean (standard deviation)
    		 1.590 ( 1.4746 ) 1.635 ( 0.8693 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo in DBTP
    Reporting group description
    		 Subjects received matching placebo subcutaneously (SC) every 2 weeks (Q2W) from baseline (Day 1) through Week 10 during the double-blind treatment period.

    Reporting group title
    Alirocumab 150 mg SC Q2W in DBTP
    Reporting group description
    		 Subjects in this arm received alirocumab 150 milligrams (mg) SC Q2W from baseline (Day 1) through Week 10 during the double-blind treatment period.
    Reporting group title
    Placebo in DBTP
    Reporting group description
    		 Subjects received matching placebo subcutaneously (SC) every 2 weeks (Q2W) from baseline (Day 1) through Week 10 during the double-blind treatment period. Starting at Week 12, and continuing through Week 22, all subjects received open-label alirocumab SC Q2W

    Reporting group title
    Alirocumab 150 mg SC Q2W
    Reporting group description
    		 Subjects in this arm received alirocumab 150 milligrams (mg) SC Q2W from baseline (Day 1) through Week 10 during the double-blind treatment period. Starting at Week 12, and continuing through Week 22, all subjects received open-label alirocumab SC Q2W

    Subject analysis set title
    Alirocumab 150 mg SC Q2W in OLTP
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received at least 1 dose or part of a dose of open-label investigational study drug alirocumab in OLTP

    Primary: Percent change in low-density lipoprotein cholesterol (LDL-C) from baseline to week 12 (Intent-to-Treat [ITT] estimand)

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    End point title
    		 Percent change in low-density lipoprotein cholesterol (LDL-C) from baseline to week 12 (Intent-to-Treat [ITT] estimand)
    End point description
    The percent change in LDL-C from baseline to week 12 is defined as: 100x (LDL-C value at week 12 - LDL-C value at baseline) / LDL-C value at baseline.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    8.6 ( 6.3 )
    -26.9 ( 4.6 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 MMRM
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    -35.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.2
         upper limit
    		 -19.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.8
    Notes
    [1] - P-value taken from MMRM (mixed-effect model with repeated measures) analysis

    Secondary: Percent change in apolipoprotein (Apo) B from baseline to week 12 (ITT estimand)

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    End point title
    		 Percent change in apolipoprotein (Apo) B from baseline to week 12 (ITT estimand)
    End point description
    ITT estimand; The percent change in Apo B from baseline to week 12 is defined as: 100x (Apo B value at week 12 - Apo B value at baseline) / Apo B value at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    7.2 ( 5.0 )
    -22.5 ( 3.7 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 MMRM
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    -29.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.3
         upper limit
    		 -17.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.3
    Notes
    [2] - p-value taken from MMRM (mixed-effect model with repeated measures) analysis

    Secondary: Percent change in non-high-density lipoprotein cholesterol (non-HDL-C) from baseline to week 12

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    End point title
    		 Percent change in non-high-density lipoprotein cholesterol (non-HDL-C) from baseline to week 12
    End point description
    ITT estimand; The percent change in non-HDL-C from baseline to week 12 is defined as: 100x (non-HDL-C value at week 12 - non-HDL-C value at baseline) / non-HDL-C value at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    8.0 ( 5.9 )
    -24.8 ( 4.3 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 MMRM
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    -32.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -47.6
         upper limit
    		 -18.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.4
    Notes
    [3] - P-value taken from MMRM (mixed-effect model with repeated measures) analysis

    Secondary: Percent change in total cholesterol (TC) from baseline to week 12

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    End point title
    		 Percent change in total cholesterol (TC) from baseline to week 12
    End point description
    ITT estimand; The percent change in TC from baseline to week 12 is defined as: 100x (TC value at week 12 - TC value at baseline) / TC value at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    6.6 ( 5.0 )
    -19.8 ( 3.7 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 MMRM
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    -26.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.9
         upper limit
    		 -14
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.2
    Notes
    [4] - P-value taken from MMRM (mixed-effect model with repeated measures) analysis.

    Secondary: Proportion of subjects with ≥15% reduction in LDL-C at week 12

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    End point title
    		 Proportion of subjects with ≥15% reduction in LDL-C at week 12
    End point description
    ITT estimand
    End point type
    Secondary
    End point timeframe
    At Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        number (not applicable)
    12.5
    61.9
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    12.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.1
         upper limit
    		 48.8

    Secondary: Proportion of subjects with ≥30% reduction in LDL-C at week 12

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    End point title
    		 Proportion of subjects with ≥30% reduction in LDL-C at week 12
    End point description
    ITT estimand
    End point type
    Secondary
    End point timeframe
    At Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        number (not applicable)
    4.2
    57.1
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Log odds ratio
    Point estimate
    36.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.3
         upper limit
    		 308.9

    Secondary: Percent change in lipoprotein(a) [Lp(a)] from baseline to week 12

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    End point title
    		 Percent change in lipoprotein(a) [Lp(a)] from baseline to week 12
    End point description
    ITT estimand; The percent change in Lp(a) from baseline to week 12 is defined as: 100x (Lp(a) value at week 12 - Lp(a) value at baseline) / Lp(a) value at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    8.8 ( 5.4 )
    -19.6 ( 4.0 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -28.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.5
         upper limit
    		 -15.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.7

    Secondary: Proportion of subjects with ≥50% reduction in LDL-C at week 12

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    End point title
    		 Proportion of subjects with ≥50% reduction in LDL-C at week 12
    End point description
    ITT estimand
    End point type
    Secondary
    End point timeframe
    At Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        number (not applicable)
    0
    26.7
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0017
    Method
    		 Exact Conditional Logistic Regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    17.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.3
         upper limit
    		 99999

    Secondary: Percent change in HDL-C from baseline to week 12 - ITT analysis

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    End point title
    		 Percent change in HDL-C from baseline to week 12 - ITT analysis
    End point description
    ITT estimand; The percent change in HDL-C from baseline to week 12 is defined as: 100x (HDL-C value at week 12 - HDL-C value at baseline) / HDL-C value at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    2.7 ( 3.1 )
    6.3 ( 2.3 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3541 [5]
    Method
    		 MMRM
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 11.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.8
    Notes
    [5] - P-value taken from MMRM (mixed-effect model with repeated measures) analysis.

    Secondary: Percent change in fasting triglycerides (TG) from baseline to week 12

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    End point title
    		 Percent change in fasting triglycerides (TG) from baseline to week 12
    End point description
    ITT estimand; The percent change in TG from baseline to week 12 is defined as: 100x (TG value at week 12 - TG value at baseline) / TG value at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    3.9 ( 5.7 )
    -7.4 ( 4.2 )
    Statistical analysis title
    		 Alirocumab 150 SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -11.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.2
         upper limit
    		 2.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.1

    Secondary: Percent change in Apo A-1 from baseline to week 12 -- ITT analysis

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    End point title
    		 Percent change in Apo A-1 from baseline to week 12 -- ITT analysis
    End point description
    ITT estimand; The percent change in Apo A-1 from baseline to week 12 is defined as: 100x (Apo A-1 value at week 12 - Apo A-1 value at baseline) / Apo A-1 value at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    1.4 ( 2.9 )
    5.0 ( 2.1 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 10.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.6

    Secondary: Percent change in LDL-C from baseline to week 12 (on-treatment estimand)

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    End point title
    		 Percent change in LDL-C from baseline to week 12 (on-treatment estimand)
    End point description
    Percent change for LDL-C from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label investigational study drug, whichever is earlier.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    8.6 ( 6.3 )
    -26.9 ( 4.6 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    -35.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.2
         upper limit
    		 -19.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.8

    Secondary: Percent change in Apo B from baseline to week 12 (on-treatment estimand)

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    End point title
    		 Percent change in Apo B from baseline to week 12 (on-treatment estimand)
    End point description
    Percent change for Apo B from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label nvestigational study drug, whichever is earlier.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    7.2 ( 5.0 )
    -22.5 ( 3.7 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    -29.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -43.3
         upper limit
    		 -17.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.3

    Secondary: Percent change in non-HDL-C from baseline to week 12 (on-treatment estimand)

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    End point title
    		 Percent change in non-HDL-C from baseline to week 12 (on-treatment estimand)
    End point description
    Percent change for non-HDL-C from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label investigational study drug, whichever is earlier.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    8.0 ( 5.9 )
    -24.8 ( 4.3 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    -32.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -47.6
         upper limit
    		 -18.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.4

    Secondary: Percent change in TC from baseline to week 12 (on-treatment estimand)

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    End point title
    		 Percent change in TC from baseline to week 12 (on-treatment estimand)
    End point description
    Percent change for TC from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label investigational study drug, whichever is earlier.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    6.6 ( 5.0 )
    -19.8 ( 3.7 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SQ Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    -26.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.9
         upper limit
    		 -14
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.2

    Secondary: Percent change in Lp(a) from baseline to week 12 (on-treatment estimand)

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    End point title
    		 Percent change in Lp(a) from baseline to week 12 (on-treatment estimand)
    End point description
    Percent change for LP(a) from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label investigational study drug, whichever is earlier.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    8.8 ( 5.4 )
    -19.6 ( 4.0 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -28.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.5
         upper limit
    		 -15.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.7

    Secondary: Percent change in HDL-C from baseline to week 12 - (on-treatment estimand)

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    End point title
    		 Percent change in HDL-C from baseline to week 12 - (on-treatment estimand)
    End point description
    Percent change for HDL-C from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label investigational study drug, whichever is earlier.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    2.7 ( 3.1 )
    6.3 ( 2.3 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 11.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.8

    Secondary: Percent change in fasting TG from baseline to week 12 (on-treatment estimand)

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    End point title
    		 Percent change in fasting TG from baseline to week 12 (on-treatment estimand)
    End point description
    Percent change for fasting TG from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label investigational study drug, whichever is earlier.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    3.9 ( 5.7 )
    -7.4 ( 4.2 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -11.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.2
         upper limit
    		 2.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.1

    Secondary: Percent change in Apo A-1 from baseline to week 12 -- (on-treatment estimand)

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    End point title
    		 Percent change in Apo A-1 from baseline to week 12 -- (on-treatment estimand)
    End point description
    Percent change for Apo A-1 from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label investigational study drug, whichever is earlier.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    1.4 ( 2.9 )
    5.0 ( 2.1 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 10.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.6

    Secondary: Proportion of subjects with ≥15% reduction, ≥30% reduction, and ≥50% reduction in LDL-C at week 12 (on-treatment estimand)

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    End point title
    		 Proportion of subjects with ≥15% reduction, ≥30% reduction, and ≥50% reduction in LDL-C at week 12 (on-treatment estimand)
    End point description
    End point type
    Secondary
    End point timeframe
    At Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
    number (not applicable)
        ≥ 15%
    12.5
    61.9
        ≥ 30%
    4.2
    57.1
        ≥ 50%
    0
    26.7
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Statistical analysis description
    ≥ 15% reduction
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    12.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.1
         upper limit
    		 48.8
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Statistical analysis description
    ≥ 30% reduction
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    36.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.3
         upper limit
    		 308.9
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Statistical analysis description
    ≥ 50% reduction
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    17.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.3
         upper limit
    		 99999

    Secondary: Absolute change in the ratio of Apo B/Apo A-1 from baseline to week 12 (ITT estimand)

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    End point title
    		 Absolute change in the ratio of Apo B/Apo A-1 from baseline to week 12 (ITT estimand)
    End point description
    ITT estimand
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    45
    Units: Percentage
        least squares mean (standard error)
    0.0 ( 0.1 )
    -0.3 ( 0.1 )
    Statistical analysis title
    		 Alirocumab 150 mg SC Q2W vs. Placebo SC Q2W
    Comparison groups
    Placebo in DBTP v Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1

    Secondary: Incidence of anti-drug antibodies (ADA) to REGN727 over time

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    End point title
    		 Incidence of anti-drug antibodies (ADA) to REGN727 over time [6]
    End point description
    End point type
    Secondary
    End point timeframe
    26 weeks
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be summarized only for reported treatment group (s) in the table.
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP
    Number of subjects analysed
    24
    44
    Units: Subjects
        Treatment-Emergent
    1
    1
    No statistical analyses for this end point

    Secondary: Incidence of Adverse Events (AEs)

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    End point title
    		 Incidence of Adverse Events (AEs)
    End point description
    All AEs will be recorded from time of informed consent to end of study. Only treatment-emergent adverse events (TEAE) will be reported. Double-blind TEAE observation period is defined as time from first dose of double-blind study drug to last dose of double-blind study drug +70 days, or up to day before first dose of open-label study drug administration, whichever is earlier. Open-label TEAE observation period is defined as time from first open-label study treatment administration to last open-label study treatment administration +70 days.
    End point type
    Secondary
    End point timeframe
    Baseline to week 32 (End of Study)
    End point values
    		 Placebo in DBTP Alirocumab 150 mg SC Q2W in DBTP Alirocumab 150 mg SC Q2W in OLTP
    Number of subjects analysed
    24
    45
    69
    Units: Subjects
        Subjects with any TEAE
    12
    20
    24
        Subjects with TEAE Serious Adverse Event (SAE)
    0
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Day 1) to end of study (Day 225)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo SC Q2W in DBTP and Alirocumab 150 mg SC Q2W in OLTP
    Reporting group description
    		 Participants received matching placebo subcutaneously (SC) every 2 weeks (Q2W) from baseline (Day 1) through Week 10 during the double-blind treatment period. Starting at Week 12, and continuing through Week 22, all participants received open-label alirocumab SC Q2W

    Reporting group title
    Alirocumab 150 Q2W in DBTP and OLTP
    Reporting group description
    		 Participants in this arm received alirocumab 150 milligrams (mg) SC Q2W from baseline (Day 1) through Week 10 during the double-blind treatment period. Starting at Week 12, and continuing through Week 22, all participants received open-label alirocumab SC Q2W

    Serious adverse events
    		 Placebo SC Q2W in DBTP and Alirocumab 150 mg SC Q2W in OLTP Alirocumab 150 Q2W in DBTP and OLTP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 45 (2.22%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo SC Q2W in DBTP and Alirocumab 150 mg SC Q2W in OLTP Alirocumab 150 Q2W in DBTP and OLTP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 24 (25.00%)
    14 / 45 (31.11%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 24 (8.33%)
    3 / 45 (6.67%)
         occurrences all number
    10
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 24 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Epistaxis
         subjects affected / exposed
    0 / 24 (0.00%)
    3 / 45 (6.67%)
         occurrences all number
    0
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 24 (4.17%)
    5 / 45 (11.11%)
         occurrences all number
    1
    7
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 24 (8.33%)
    2 / 45 (4.44%)
         occurrences all number
    3
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Mar 2017
    Refining diagnostic criteria; adding additional assessments; sample size adjustment in statistical methods; correct inconsistencies and make additional editorial changes
    11 Jul 2017
    Added exclusion criteria; extended treatment emergent AE period; clarified text and added definitions; added an assessment for hepatitis C and process instructions; edits and clarifications.
    04 Jan 2019
    Increased sample size; revised ITT population definition

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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