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    Clinical Trial Results:
    A Phase 2 Pilot Study with a Randomized Double-Blind Treatment Phase to Evaluate the Pharmacodynamics and Safety of Alirocumab in Patients with Autosomal Dominant Hypercholesterolemia and Gain-of-Function Mutations in 1 or Both Alleles of the PCSK9 Gene or Loss-of-Function Mutations in 1 or More Alleles of the Apolipoprotein B Gene

    Summary
    EudraCT number
    2011-004308-39
    Trial protocol
    FR  
    Global end of trial date
    28 Jul 2017

    Results information
    Results version number
    v1
    This version publication date
    04 Aug 2019
    First version publication date
    04 Aug 2019
    Other versions
    v2

    Trial information

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    Trial identification
    Sponsor protocol code
    R727-CL-1018
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01604824
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals
    Sponsor organisation address
    777 Old Saw Mill, Tarrytown, United States, 10591
    Public contact
    Clinical Trial Management, Regeneron Pharmaceuticals, clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trial Management, Regeneron Pharmaceuticals, 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
    24 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the pharmacodynamic effect of alirocumab on serum low-density lipoprotein cholesterol (LDL-C) during 14 weeks of subcutaneous (SC) administered alirocumab in subjects with autosomal dominant hypersholesterolemia (ADH) and gain-of-function mutations (GOFm) in 1 or both alleles of the proprotein convertase subtilisin kexin 9 (PCSK9) gene or with loss-of-function mutations (LOFm) in 1 or more alleles of the apolipoprotein (Apo B) gene.
    Protection of trial subjects
    This 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 Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    Stable lipid-lowering therapies (LLT) included, but not limited to statins, ezetimibe, fibrates, niacin, omega-3 fatty acids, and bile acid resins.
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Feb 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    United States: 15
    Worldwide total number of subjects
    23
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    23
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at three sites in France & one in the US. Twenty-eight subjects were screened between Feb 2012 & Apr 2013. A total of 23 subjects were enrolled: 13 in cohort 1 and 10 in cohort 2. Recruitment for cohort 2 occurred after the un-blinding of cohort 1 and analyses of the double-blind study data for cohort 1.

    Pre-assignment
    Screening details
    Eligible subjects entered a 2-week, single-blind, placebo run-in period (day -14). Cohort 1 (subjects with gain of function mutation [GOFm] in PCSK9 gene) was randomized in a 1:1 ratio (group A or B); cohort 2 (subjects with GOFm in PCSK9 gene or a loss of function mutation [LOFm] in ApoB gene) was also randomized in a 1:1 ratio (group C or D).

    Period 1
    Period 1 title
    Double-blind (DB) Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Carer, Assessor, Subject
    Blinding implementation details
    The double-blind study period includes a double-blind treatment period from visit 3 (day 1) to visit 11 (week 14) and a follow-up period to visit 15 (week 22)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A)
    Arm description
    Subjects with a gain-of-function mutation (GOFm) in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    REGN727/SAR236553
    Other name
    Praluent
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Alirocumab 150 mg administered as a SC injection of 1 mL into the abdomen

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo administered as a SC injection of 1 mL into the abdomen

    Arm title
    PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B)
    Arm description
    Subjects with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo administered as a SC injection of 1 mL into the abdomen

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    REGN727/SAR236553
    Other name
    Praluent
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Alirocumab 150 mg administered as a SC injection of 1 mL into the abdomen

    Arm title
    PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C)
    Arm description
    Subjects with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    REGN727/SAR236553
    Other name
    Praluent
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Alirocumab 150 mg administered as a SC injection of 1 mL into the abdomen

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo administered as a SC injection of 1 mL into the abdomen

    Arm title
    PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2: Group D)
    Arm description
    Subjects with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    REGN727/SAR236553
    Other name
    Praluent
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Alirocumab 150 mg administered as a SC injection of 1 mL into the abdomen

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo administered as a SC injection of 1 mL into the abdomen

    Number of subjects in period 1
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A) PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B) PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C) PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2: Group D)
    Started
    6
    7
    5
    5
    Completed DB Period (Day 99)
    6
    7
    5
    5
    Completed DB Follow-up (Day 155)
    6
    7
    5
    5
    Completed
    6
    7
    5
    5
    Period 2
    Period 2 title
    Open-label Extension (OLE) Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    PCSK9 GOFm (Cohort 1: Group A and Group B)
    Arm description
    Subjects with a GOFm in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Subjects with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC, Q2W for an additional 3 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    REGN727/SAR236553
    Other name
    Praluent
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Alirocumab 150 mg administered as a SC injection of 1 mL into the abdomen

    Arm title
    PCSK9 GOFm/ApoB LOFm (Cohort 2: Group C and Group D)
    Arm description
    Subjects with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Subjects with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Afterwards, subjects had the possibility to continue in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    REGN727/SAR236553
    Other name
    Praluent
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Alirocumab 150 mg administered as a SC injection of 1 mL into the abdomen

    Number of subjects in period 2
    PCSK9 GOFm (Cohort 1: Group A and Group B) PCSK9 GOFm/ApoB LOFm (Cohort 2: Group C and Group D)
    Started
    13
    10
    Started Open-label Extension Period
    11
    10
    Completed Study
    10
    10
    Completed
    10
    10
    Not completed
    3
    0
         Chose not to enter OLE Period
    2
    -
         Refused to come into office
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A)
    Reporting group description
    Subjects with a gain-of-function mutation (GOFm) in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.

    Reporting group title
    PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B)
    Reporting group description
    Subjects with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.

    Reporting group title
    PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C)
    Reporting group description
    Subjects with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.

    Reporting group title
    PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2: Group D)
    Reporting group description
    Subjects with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.

    Reporting group values
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A) PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B) PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C) PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2: Group D) Total
    Number of subjects
    6 7 5 5 23
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    6 7 5 5 23
        From 65-84 years
    0 0 0 0 0
        85 years and over
    0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    42.3 ± 14.72 46.4 ± 13.24 45.6 ± 3.21 42.0 ± 10.84 -
    Gender, Male/Female
    Units: Subjects
        Male
    2 2 1 3 8
        Female
    4 5 4 2 15
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 0 0 0 0
        Not Hispanic or Latino
    6 7 5 5 23
    Race (NIH/OMB)
    Units: Subjects
        White
    5 6 5 5 21
        Black or African American
    0 0 0 0 0
        Asian
    0 0 0 0 0
        American Indian or Alaska Native
    0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0
        Other: Indian Ocean Islander
    0 1 0 0 1
        Other: Mauritius
    1 0 0 0 1
    Measured Low-Density Lipoprotein Cholesterol (LDL-C)
    Baseline value is defined as the last available value prior to the first dose of double-blind period (alirocumab or placebo).
    Units: milligrams per deciliter (mg/dL)
        arithmetic mean (standard deviation)
    108.8 ± 33.84 144.3 ± 68.39 187.4 ± 98.12 151.0 ± 82.70 -
    Total Cholesterol
    Baseline value is defined as the last available value prior to the first dose of double-blind period (alirocumab or placebo).
    Units: mg/dL
        arithmetic mean (standard deviation)
    181.3 ± 41.89 216.3 ± 78.61 249.8 ± 86.68 226.0 ± 77.80 -
    Non-high-density lipoprotein cholesterol (Non-HDL-C)
    Baseline value is defined as the last available value prior to the first dose of double-blind period (alirocumab or placebo).
    Units: mg/dL
        arithmetic mean (standard deviation)
    124.3 ± 49.00 165.9 ± 75.59 189.4 ± 93.43 163.4 ± 86.88 -
    Apolipoprotein (Apo) B100
    Baseline value is defined as the last available value prior to the first dose of double-blind period (alirocumab or placebo).
    Units: mg/dL
        arithmetic mean (standard deviation)
    89.2 ± 27.29 101.0 ± 15.77 129.4 ± 58.27 103.6 ± 42.83 -
    Apolipoprotein (Apo) A1
    Baseline value is defined as the last available value prior to the first dose of double-blind period (alirocumab or placebo).
    Units: mg/dL
        arithmetic mean (standard deviation)
    136.3 ± 29.75 131.4 ± 30.02 154.0 ± 10.98 154.8 ± 20.36 -

    End points

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    End points reporting groups
    Reporting group title
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A)
    Reporting group description
    Subjects with a gain-of-function mutation (GOFm) in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.

    Reporting group title
    PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B)
    Reporting group description
    Subjects with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.

    Reporting group title
    PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C)
    Reporting group description
    Subjects with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.

    Reporting group title
    PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2: Group D)
    Reporting group description
    Subjects with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.
    Reporting group title
    PCSK9 GOFm (Cohort 1: Group A and Group B)
    Reporting group description
    Subjects with a GOFm in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Subjects with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC, Q2W for an additional 3 years.

    Reporting group title
    PCSK9 GOFm/ApoB LOFm (Cohort 2: Group C and Group D)
    Reporting group description
    Subjects with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Subjects with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Afterwards, subjects had the possibility to continue in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.

    Primary: Percent Change in Measured Serum Low-Density Lipoprotein Cholesterol (LDL-C) from Baseline to Day 15

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    End point title
    Percent Change in Measured Serum Low-Density Lipoprotein Cholesterol (LDL-C) from Baseline to Day 15
    End point description
    By day 15, subjects in groups A and C had received 1 subcutaneous (SC) dose of 150 mg alirocumab and subjects in group B and D had received 1 SC dose of placebo. [Baseline adjusted least squares (LS) means and standard errors were obtained using analysis of covariance (ANCOVA) model specifying the treatment arm as the fixed effect and the baseline measured LDL-C value as a covariate.]
    End point type
    Primary
    End point timeframe
    Baseline to Day 15
    End point values
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A) PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B) PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C) PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2: Group D)
    Number of subjects analysed
    6 [1]
    7 [2]
    5 [3]
    5 [4]
    Units: percent change
        least squares mean (standard error)
    -62.48 ± 8.217
    -8.77 ± 7.575
    -48.21 ± 7.660
    -4.93 ± 7.660
    Notes
    [1] - By day 15, subjects in group A had received 1 SC dose of 150 mg alirocumab
    [2] - By day 15, subjects in group B had received 1 SC dose of placebo
    [3] - By day 15, subjects in group C had received 1 SC dose of 150 mg alirocumab
    [4] - By day 15, subjects in group D had received 1 SC dose of placebo
    Statistical analysis title
    Alirocumab (Group A) vs Placebo (Group B)
    Comparison groups
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A) v PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0009 [5]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -53.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -79.31
         upper limit
    -28.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.486
    Notes
    [5] - Threshold for significance ≤ 0.05
    Statistical analysis title
    Alirocumab (Group C) vs Placebo (Group D)
    Comparison groups
    PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C) v PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2: Group D)
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0056 [6]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -43.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -69.21
         upper limit
    17.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.965
    Notes
    [6] - Threshold for significance ≤ 0.05

    Secondary: Percent Change in Apolipoprotein (Apo) B100 from Baseline to Day 15

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    End point title
    Percent Change in Apolipoprotein (Apo) B100 from Baseline to Day 15
    End point description
    Baseline adjusted LS means and standard errors were obtained using the same ANCOVA model as for primary endpoint specifying the treatment arm as the fixed effect and the parameter value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 15
    End point values
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A) PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B) PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C) PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2: Group D)
    Number of subjects analysed
    6 [7]
    7 [8]
    5 [9]
    5 [10]
    Units: percent change
    least squares mean (standard error)
        Apo B100
    -53.33 ± 8.678
    -3.78 ± 8.008
    -47.73 ± 7.547
    -3.09 ± 7.547
    Notes
    [7] - By day 15, subjects in group A had received 1 SC dose of 150 mg alirocumab
    [8] - By day 15, subjects in group B had received 1 SC dose of placebo
    [9] - By day 15, subjects in group C had received 1 SC dose of 150 mg alirocumab
    [10] - By day 15, subjects in group D had received 1 SC dose of placebo
    Statistical analysis title
    Alirocumab (Group A) vs Placebo (Group B)
    Statistical analysis description
    LS means (SE), mean difference, 95% CI, and p-values were derived from ANCOVA with treatment group as factor and baseline as covariate.
    Comparison groups
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A) v PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0021 [11]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -49.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -76.39
         upper limit
    -22.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    12.05
    Notes
    [11] - Threshold for significance ≤ 0.05
    Statistical analysis title
    Alirocumab (Group C) vs Placebo (Group D)
    Statistical analysis description
    LS means (SE), mean difference, 95% CI, and p-values were derived from ANCOVA with treatment group as factor and baseline as covariate.
    Comparison groups
    PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2: Group D) v PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C)
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0045 [12]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -44.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -70.36
         upper limit
    18.92
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.876
    Notes
    [12] - Threshold for significance ≤ 0.05

    Secondary: Percent Change in Non High-Density Lipoprotein Cholesterol (Non-HDL-C) from Baseline to Day 15

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    End point title
    Percent Change in Non High-Density Lipoprotein Cholesterol (Non-HDL-C) from Baseline to Day 15
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Day 15
    End point values
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A) PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B) PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C) PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2: Group D)
    Number of subjects analysed
    6 [13]
    7 [14]
    5 [15]
    5 [16]
    Units: percent change
    least squares mean (standard error)
        Non-HDL-C
    -56.87 ± 8.217
    -7.50 ± 7.575
    -44.40 ± 7.357
    -4.04 ± 7.357
    Notes
    [13] - By day 15, subjects in group A had received 1 SC dose of 150 mg alirocumab
    [14] - By day 15, subjects in group B had received 1 SC dose of placebo
    [15] - By day 15, subjects in group C had received 1 SC dose of 150 mg alirocumab
    [16] - By day 15, subjects in group D had received 1 SC dose of placebo
    Statistical analysis title
    Alirocumab (Group A) vs Placebo (Group B)
    Comparison groups
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A) v PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0016 [17]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -49.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -74.96
         upper limit
    -23.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.487
    Notes
    [17] - Threshold for significance ≤ 0.05
    Statistical analysis title
    Alirocumab (Group C) vs Placebo (Group D)
    Comparison groups
    PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C) v PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2: Group D)
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0063 [18]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -40.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -65.12
         upper limit
    15.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.471
    Notes
    [18] - Threshold for significance ≤ 0.05

    Secondary: Percent Change in Total Cholesterol (Total-C) from Baseline to Day 15

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    End point title
    Percent Change in Total Cholesterol (Total-C) from Baseline to Day 15
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Day 15
    End point values
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A) PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B) PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C) PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2: Group D)
    Number of subjects analysed
    6 [19]
    7 [20]
    5 [21]
    5 [22]
    Units: percent change
    least squares mean (standard error)
        Total-C
    -36.94 ± 5.203
    -6.18 ± 4.802
    -29.40 ± 4.422
    -7.18 ± 4.422
    Notes
    [19] - By day 15, subjects in group A had received 1 SC dose of 150 mg alirocumab
    [20] - By day 15, subjects in group B had received 1 SC dose of placebo
    [21] - By day 15, subjects in group C had received 1 SC dose of 150 mg alirocumab
    [22] - By day 15, subjects in group D had received 1 SC dose of placebo
    Statistical analysis title
    Alirocumab (Group A) vs Placebo (Group B)
    Comparison groups
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A) v PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0017 [23]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -30.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -46.85
         upper limit
    -14.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.224
    Notes
    [23] - Threshold for significance ≤ 0.05
    Statistical analysis title
    Alirocumab (Group C) vs Placebo (Group D)
    Comparison groups
    PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C) v PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2: Group D)
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0096 [24]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -22.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -37.11
         upper limit
    -7.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.294
    Notes
    [24] - Threshold for significance ≤ 0.05

    Secondary: Percent Change in Apolipoprotein (Apo) B100/ ApoA-1 Ratio from Baseline to Day 15

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    End point title
    Percent Change in Apolipoprotein (Apo) B100/ ApoA-1 Ratio from Baseline to Day 15
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Day 15
    End point values
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A) PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B) PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C) PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2: Group D)
    Number of subjects analysed
    6 [25]
    7 [26]
    5 [27]
    5 [28]
    Units: percent change
    least squares mean (standard error)
        ApoB100/ApoA-1 Ratio
    -55.26 ± 7.188
    -5.53 ± 6.647
    -48.34 ± 8.090
    0.99 ± 8.090
    Notes
    [25] - By day 15, subjects in group A had received 1 SC dose of 150 mg alirocumab
    [26] - By day 15, subjects in group B had received 1 SC dose placebo
    [27] - By day 15, subjects in group C had received 1 SC dose of 150 mg alirocumab
    [28] - By day 15, subjects in group D had received 1 SC dose of placebo
    Statistical analysis title
    Alirocumab (Group A) vs Placebo (Group B)
    Comparison groups
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A) v PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005 [29]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -49.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -71.71
         upper limit
    -27.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.867
    Notes
    [29] - Threshold for significance ≤ 0.05
    Statistical analysis title
    Alirocumab (Group C) vs Placebo (Group D)
    Comparison groups
    PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C) v PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2: Group D)
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0037 [30]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -49.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -76.63
         upper limit
    -22.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.545
    Notes
    [30] - Threshold for significance ≤ 0.05

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the screening visit after the last alirocumab injection in the open-label period + 70 days through the end of study
    Adverse event reporting additional description
    Observation periods for safety analyses: Pretreatment: screening to before 1st injection of alirocumab; Double-blind (DB) treatment-emergent (TE): after 1st through last in DB+70 days; Interim: after last in DB+70 days prior to 1st in open-label (OL). OL TE: after 1st through last in OL+70 days. Post: after last in OL+70 days through end of study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A)
    Reporting group description
    Double-blind Period: Subjects with a GOFm in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.

    Reporting group title
    PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B)
    Reporting group description
    Subjects with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.

    Reporting group title
    PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C)
    Reporting group description
    Subjects with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.

    Reporting group title
    PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2:Group D)
    Reporting group description
    Subjects with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.

    Reporting group title
    OLE Period: PCSK9 GOFm (Cohort 1) Group A & Group B
    Reporting group description
    Subjects with a GOFm in PCSK9 gene (Cohort 1): alirocumab 150 mg subcutaneous (SC) injection at Week 0 (Day 1), Week 2 (Day 15), Weeks 4, 6 and 10 (matching placebo at Week 8, 12 and 14) during the double-blind period (Group A) or at Week 2 (Day 15), Weeks 4, 6, 8 and 12 (matching placebo at Week 0 [Day 1], Weeks 10 and 14) during the double-blind period (Group B). Afterwards, subjects continued in an OLE period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.

    Reporting group title
    OLE Period: PCSK9 GOFm/ ApoB LOFm (Cohort 2) Group C & Group D
    Reporting group description
    Subjects with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2): alirocumab 150 mg SC injection at Week 0 (Day 1), Week 2 (Day 15), Weeks 4, 6 and 10 (matching placebo at Weeks 8, 12 and 14) during the double-blind period (Group C) or at Week 2 (Day 15), Weeks 4, 6, 8 and 12 (matching placebo at Week 0 [Day 1], 10 and 14) during the double-blind period (Group D). Afterwards, subjects continued in an OLE period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.

    Serious adverse events
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A) PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B) PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C) PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2:Group D) OLE Period: PCSK9 GOFm (Cohort 1) Group A & Group B OLE Period: PCSK9 GOFm/ ApoB LOFm (Cohort 2) Group C & Group D
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    3 / 11 (27.27%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Salivary gland disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Obesity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    PCSK9 GOFm: Alirocumab from Day 1 (Cohort 1: Group A) PCSK9 GOFm: Alirocumab from Day 15 (Cohort 1: Group B) PCSK9 GOFm/ApoB LOFm: Alirocumab from Day1 (Cohort 2: Group C) PCSK9GOFm/ApoB LOFm: Alirocumab from Day 15(Cohort 2:Group D) OLE Period: PCSK9 GOFm (Cohort 1) Group A & Group B OLE Period: PCSK9 GOFm/ ApoB LOFm (Cohort 2) Group C & Group D
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    6 / 7 (85.71%)
    5 / 5 (100.00%)
    4 / 5 (80.00%)
    10 / 11 (90.91%)
    9 / 10 (90.00%)
    Vascular disorders
    Raynaud's phenomenon
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Diabetic vascular disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pituitary tumour benign
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    10
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    Asthenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    Inflammation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Cardiac procedure complication
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Joint dislocation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Muscle strain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nitrite urine present
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    White blood cells urine positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    3
    0
    Angina unstable
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Prinzmetal angina
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    Hypoxia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    0
    Migraine
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Sciatica
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Amnesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nerve compression
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Ear pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Aphthous ulcer
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Dyspesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Functional gastrointestinal disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Urinary retention
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hepatobiliary disorders
    Hepatic steatosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Acne
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    1
    1
    0
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Dermatitis allergic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Peau d'orange
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Back pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tendonitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Endocrine disorders
    Thyroid mass
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vitamin B complex deficiency
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    1
    0
    0
    2
    Influenza
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    0
    1
    1
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    4
    1
    Pneumonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    2 / 10 (20.00%)
         occurrences all number
    1
    1
    0
    0
    1
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    2 / 5 (40.00%)
    1 / 5 (20.00%)
    4 / 11 (36.36%)
    2 / 10 (20.00%)
         occurrences all number
    3
    1
    4
    1
    6
    2
    Cystitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Diverticulitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Ear infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infectious mononucleosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Kidney infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Localised infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Otitis externa
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Sialoadenitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tooth infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Mar 2012
    The purpose of this amendment was to: - Update the eligibility criteria to exclude subjects with a known history of active optic nerve disease. - Clarify that subjects who experienced acute injection reactions of clinical concern would be permanently discontinued from study drug.
    02 Apr 2012
    The purpose of this amendment was to: - Add a phone call visit (PV5) between visit 5 and visit 6 to ensure the safety of subjects who received their first dose of alirocumab on study day 15 (visit 5). - Remove ribonucleic acid (RNA) sample collection from the study.- Add 2 additional research sample collections to facilitate exploratory research on novel biomarkers. - Remove the pharmacokinetic (PK) sample collection at the screening visit and added an Anti-drug antibody (ADA) sample collection at the screening visit. - Add a request that subjects who were prematurely discontinued from study drug return to the clinic for all remaining study visits’. - Update information about the safety and efficacy for the 3 phase 2 studies in the introduction section. - Update information regarding the requirement that any subject who experienced an acute injection reaction of clinical concern would be permanently discontinued from study drug. - Make clarifications, minor corrections, and administrative changes.
    31 Oct 2012
    The purpose of this amendment was to: - Extend the study to include an open-label treatment period for approximately 3 years or until approval of the product. - Add an interim analysis to the study. - Add an independent data monitoring committee (DMC) to the study. - Add an adjudication committee to adjudicate any cardiovascular events that occurred during the study. - Remove “oral” from the body temperature evaluations. - Make clarifications, corrections, and administrative changes.
    21 Jan 2013
    The purpose of this amendment was to: - Update information regarding the independent DMC. - Specify that use of red yeast rice was prohibited during the study. - Add additional flow charts to manage AEs and abnormal laboratory values. - Make clarifications, minor corrections, and administrative changes.
    23 Jun 2013
    The purpose of this amendment was to: - Include an additional cohort consisting of subjects with Autosomal dominant hypercholesterolemia (ADH) and GOFm in 1 or both alleles of the PCSK9 gene or subjects with LOFm in the Apo B gene (approximately 20 subjects were to be randomized to groups C and D in a 1:1 ratio and subjected to the identical assessments and procedures described for groups A and B in the previous amendment). - Update the document by substituting the non-proprietary name, alirocumab, for REGN727. - Make clarifications, minor corrections, and administrative changes.

    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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