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    Clinical Trial Results:
    AN 8-WEEK, OPEN-LABEL, PHASE 1 STUDY TO EVALUATE PHARMACOKINETICS, PHARMACODYNAMICS, SAFETY AND TOLERABILITY OF ATORVASTATIN IN CHILDREN AND ADOLESCENTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA

    Summary
    EudraCT number
    		 2008-002774-34
    Trial protocol
    		 NL   Outside EU/EEA  
    Global end of trial date
    13 May 2009

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 May 2016
    First version publication date
    30 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A2581172
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00739999
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer Inc., Pfizer ClinicalTrials.gov Call Center, 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer Inc., Pfizer ClinicalTrials.gov Call Center, 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000073-PIP01-07
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Aug 2009
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To develop population pharmacokinetic models for atorvastatin and its active metabolites (o-hydroxyatorvastatin and p-hydroxyatorvastatin) in children and adolescents with heterozygous familial hypercholesterolemia (HeFH), and to examine the influence of covariates on the pharmacokinetic parameters.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Dec 2008
    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
    Norway: 11
    Country: Number of subjects enrolled
    Greece: 9
    Country: Number of subjects enrolled
    Canada: 19
    Worldwide total number of subjects
    39
    EEA total number of subjects
    20
    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)
    18
    Adolescents (12-17 years)
    21
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled at 3 medical centres and participated in the study between 02 December 2008 and 13 May 2009. The enrolment in Norway, Greece and Canada.

    Pre-assignment
    Screening details
    		 Forty-five subjects were screened, and 39 subjects were assigned to study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Atorvastatin (5 mg, 10 mg): Tanner Stage 1
    Arm description
    		 Age 6 - 10 years, at Tanner Stage 1. Initial dose through Week 4; after Week 4 dose may have been doubled if target low-density lipoprotein cholesterol (LDL-C) was not attained.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atorvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Initial dose 5 mg/day through Week 4; after Week 4 dose may have been doubled to 10 mg/day if target low-density lipoprotein cholesterol (LDL-C) was not attained.

    Arm title
    		 Atorvastatin (10 mg, 20 mg): Tanner Stage 2+
    Arm description
    		 Age 10 - 17 years, at Tanner Stage 2+. Initial dose through Week 4; after Week 4 dose may have been doubled if target LDL-C was not attained.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atorvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Initial dose 10 mg/day through Week 4; after Week 4 dose may have been doubled to 20 mg/day if target LDL-C was not attained.

    Number of subjects in period 1
    		Atorvastatin (5 mg, 10 mg): Tanner Stage 1 Atorvastatin (10 mg, 20 mg): Tanner Stage 2+
    Started
    15
    24
    Completed
    15
    24

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atorvastatin (5 mg, 10 mg): Tanner Stage 1
    Reporting group description
    		 Age 6 - 10 years, at Tanner Stage 1. Initial dose through Week 4; after Week 4 dose may have been doubled if target low-density lipoprotein cholesterol (LDL-C) was not attained.

    Reporting group title
    Atorvastatin (10 mg, 20 mg): Tanner Stage 2+
    Reporting group description
    		 Age 10 - 17 years, at Tanner Stage 2+. Initial dose through Week 4; after Week 4 dose may have been doubled if target LDL-C was not attained.

    Reporting group values
    		 Atorvastatin (5 mg, 10 mg): Tanner Stage 1 Atorvastatin (10 mg, 20 mg): Tanner Stage 2+ Total
    Number of subjects
    		 15 24 39
    Age categorical
    Units: Subjects
        6-8 years
    		 7 0 7
        9-10 years
    		 6 3 9
        11-14 years
    		 2 14 16
        15-17 years
    		 0 7 7
    Gender categorical
    Units: Subjects
        Female
    		 7 12 19
        Male
    		 8 12 20

    End points

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    End points reporting groups
    Reporting group title
    Atorvastatin (5 mg, 10 mg): Tanner Stage 1
    Reporting group description
    		 Age 6 - 10 years, at Tanner Stage 1. Initial dose through Week 4; after Week 4 dose may have been doubled if target low-density lipoprotein cholesterol (LDL-C) was not attained.

    Reporting group title
    Atorvastatin (10 mg, 20 mg): Tanner Stage 2+
    Reporting group description
    		 Age 10 - 17 years, at Tanner Stage 2+. Initial dose through Week 4; after Week 4 dose may have been doubled if target LDL-C was not attained.

    Subject analysis set title
    Stayed at 5 mg: Tanner Stage 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Atorvastatin 5 mg/day

    Subject analysis set title
    Titrated to 10 mg: Tanner Stage 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Atorvastatin: initial dose 5 mg/day through Week 4; after Week 4 dose was doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.

    Subject analysis set title
    Stayed at 10 mg: Tanner Stage 2+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Atorvastatin 10 mg/day

    Subject analysis set title
    Titrated to 20 mg: Tanner Stage 2+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Atorvastatin: initial dose 10 mg/day through Week 4; after Week 4 dose was doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.

    Subject analysis set title
    Atorvastatin (5 mg, 10 mg, 20 mg): Tanner Stages 1 and 2+
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Tanner Stage 1: Initial dose 5 mg/day through Week 4; after Week 4 dose may have been doubled to 10 mg/day if target LDL-C was not attained and study drug was well tolerated; Tanner Stage 2+: Initial dose 10 mg/day through Week 4; after Week 4 dose may have been doubled to 20 mg/day if target LDL-C was not attained and study drug was well tolerated.

    Primary: Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Atorvastatin Apparent Clearance (CL/F)

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    End point title
    		 Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Atorvastatin Apparent Clearance (CL/F)
    End point description
    Parent-metabolite population PK model built using sparse blood samples from both Tanner Stage 1 and Tanner Stage 2+. Blood sampling times: Weeks 2 and 6: single sample between 4 and 12 hours postdose; Weeks 4 and 8: predose, 1 hour, and 2 hours postdose. Plasma samples were analyzed for atorvastatin and active hydroxyacid metabolite (o-hydroxyatorvastatin) concentrations using a validated, sensitive, and specific high-performance liquid chromatography tandem mass spectrometric method. Data presented are the result of the model used. Pharmacokinetic (PK) concentration population: all enrolled and treated subjects who had greater than or equal to (>=) 1 PK concentration assessed. Active hydroxyacid metabolite p-hydroxyatorvastatin was not included in the model as originally planned as greater than (>) 80% of samples were below detectable level at the doses used in this trial.
    End point type
    Primary
    End point timeframe
    Week 2, Week 4, Week 6, Week 8
    End point values
    		 Atorvastatin (5 mg, 10 mg): Tanner Stage 1 Atorvastatin (10 mg, 20 mg): Tanner Stage 2+
    Number of subjects analysed
    15
    24
    Units: liter per hour (L/hr)
        number (not applicable)
    553
    543
    Statistical analysis title
    		 Atorvastatin Apparent Clearance (CL/F)
    Statistical analysis description
    Atorvastatin apparent clearance (CL/F) was described as a function of body weight using an allometric equation. The estimated parameter given is an extrapolation of the model for subjects who weigh 70 kg. Measures of parameter estimation uncertainty (95% CI) were determined by non-parametric bootstrap analysis.
    Comparison groups
    Atorvastatin (5 mg, 10 mg): Tanner Stage 1 v Atorvastatin (10 mg, 20 mg): Tanner Stage 2+
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 non-linear mixed-effects model
    Point estimate
    699
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 570
         upper limit
    		 881

    Primary: Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Apparent Volume of Distribution of the Central Compartment (Vc/F)

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    End point title
    		 Parent-metabolite Population Pharmacokinetic (PK) Model for Atorvastatin and Its Metabolites: Apparent Volume of Distribution of the Central Compartment (Vc/F) [1]
    End point description
    Parent-metabolite population PK model built using sparse blood samples from Tanner Stages 1 and 2+. Sampling times: Weeks 2 + 6: single sample between 4 -12 hours postdose; Weeks 4 + 8: predose, 1 + 2 hours postdose. Plasma samples analyzed for atorvastatin and active hydroxyacid metabolite (o-hydroxyatorvastatin) concentrations using validated, sensitive, specific high-performance liquid chromatography tandem mass spectrometric method. Vc/F value based on 70 kg body weight. Parameter estimation uncertainty (95% CI) by non-parametric bootstrap analysis. Data presented are result of model used. PK concentration population: all enrolled and treated subjects who had >= 1 PK concentration assessed. Active hydroxyacid metabolite p-hydroxyatorvastatin was not included in the model as originally planned as > 80% of samples were below detectable level at the doses used in this trial.
    End point type
    Primary
    End point timeframe
    Week 2, Week 4, Week 6, Week 8
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Inferential statistical analysis was not performed since descriptive statistical analysis was planned for this endpoint.
    End point values
    		 Atorvastatin (5 mg, 10 mg, 20 mg): Tanner Stages 1 and 2+
    Number of subjects analysed
    39
    Units: liters
        number (confidence interval 95%)
    1020 (209 to 2210)
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C)

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    End point title
    		 Absolute Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C)
    End point description
    Low-density lipoprotein cholesterol (LDL-C) measured in millimoles per liter (mmol/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline is equal to (=) value at observation minus baseline value. Pharmacodynamic (PD) analysis population: all enrolled subjects who received >= 1 dose of study drug and had >= 1 PD parameter measurement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 6, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    5
    10
    9
    15
    Units: mmol/L
    arithmetic mean (standard deviation)
        Baseline
    4.87 ± 0.48
    6.37 ± 1.1
    5.11 ± 0.65
    6.23 ± 1
        Week 2
    -1.75 ± 0.72
    -1.62 ± 0.46
    -1.95 ± 0.52
    -1.9 ± 0.72
        Week 4
    -2.07 ± 0.5
    -1.94 ± 0.56
    -2.24 ± 0.57
    -2.27 ± 1.04
        Week 6
    -1.89 ± 0.42
    -2.57 ± 0.7
    -2.12 ± 0.74
    -2.55 ± 1.02
        Week 8
    -1.8 ± 0.63
    -2.71 ± 0.6
    -1.99 ± 0.58
    -2.6 ± 1.01
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C)

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    End point title
    		 Percent Change From Baseline in Pharmacodynamic Responses of Low-density Lipoprotein Cholesterol (LDL-C)
    End point description
    Low-density Lipoprotein Cholesterol (LDL-C): percent (%) change from baseline by treatment over time = [LDL-C at observation minus LDL-C at Week 0] divided by LDL-C at Week 0 multiplied by (*) 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). PD analysis population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 6, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    5
    10
    9
    15
    Units: percent change in LDL-C
    arithmetic mean (standard deviation)
        Week 2
    -36.27 ± 14.72
    -25.7 ± 7.76
    -38.14 ± 9.35
    -30.27 ± 9.22
        Week 4
    -42.33 ± 8.24
    -30.27 ± 5.72
    -43.66 ± 7.78
    -35.13 ± 12.01
        Week 6
    -38.87 ± 7.84
    -40.01 ± 6.34
    -41.22 ± 11.34
    -39.73 ± 10.4
        Week 8
    -36.78 ± 11.16
    -42.7 ± 6.45
    -38.45 ± 7.84
    -40.39 ± 11.71
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Total Cholesterol (TC)

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    End point title
    		 Absolute Change From Baseline in Total Cholesterol (TC)
    End point description
    Total Cholesterol measured in millimoles per liter (mmol/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value. PD analysis population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 6, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    5
    10
    9
    15
    Units: mmol/L
    arithmetic mean (standard deviation)
        Baseline
    6.76 ± 0.46
    8.58 ± 1.06
    6.92 ± 0.71
    8.4 ± 1.1
        Week 2
    -1.89 ± 0.79
    -2.04 ± 0.69
    -2.11 ± 0.53
    -2.28 ± 0.82
        Week 4
    -2.27 ± 0.63
    -2.24 ± 0.49
    -2.37 ± 0.61
    -2.66 ± 1.29
        Week 6
    -2.03 ± 0.53
    -2.86 ± 0.79
    -2.28 ± 0.73
    -2.95 ± 1.19
        Week 8
    -1.89 ± 0.44
    -3.2 ± 0.65
    -2.26 ± 0.69
    -3.22 ± 1.14
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Total Cholesterol (TC)

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    End point title
    		 Percent Change From Baseline in Total Cholesterol (TC)
    End point description
    Total cholesterol (TC): percent (%) change from baseline by treatment over time = [TC at observation minus TC at Week 0] divided by TC at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). PD analysis population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 6, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    5
    10
    9
    15
    Units: percent change in TC
    arithmetic mean (standard deviation)
        Week 2
    -28.06 ± 11.23
    -24.11 ± 8.97
    -30.6 ± 7.49
    -26.78 ± 7.59
        Week 4
    -33.37 ± 7.81
    -26.12 ± 4.24
    -33.98 ± 7.13
    -30.54 ± 11.6
        Week 6
    -29.99 ± 8
    -33.12 ± 6.83
    -32.8 ± 8.97
    -34.06 ± 9.94
        Week 8
    -27.8 ± 5.56
    -37.17 ± 5.28
    -32.43 ± 8.53
    -37.45 ± 9.89
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Triglycerides (TG)

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    End point title
    		 Absolute Change From Baseline in Triglycerides (TG)
    End point description
    Change from baseline in triglycerides measured in millimoles per liter (mmol/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value. PD analysis population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 6, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    5
    10
    9
    15
    Units: mmol/L
    arithmetic mean (standard deviation)
        Baseline
    0.76 ± 0.15
    0.95 ± 0.27
    1.03 ± 0.37
    1.2 ± 0.5
        Week 2
    0.05 ± 0.34
    -0.08 ± 0.28
    0.05 ± 0.68
    0 ± 0.47
        Week 4
    -0.05 ± 0.29
    -0.26 ± 0.3
    -0.1 ± 0.51
    -0.1 ± 0.37
        Week 6
    0.4 ± 0.62
    -0.04 ± 0.24
    -0.12 ± 0.42
    -0.04 ± 0.32
        Week 8
    0.02 ± 0.28
    -0.16 ± 0.37
    -0.31 ± 0.43
    -0.28 ± 0.41
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Triglycerides (TG)

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    End point title
    		 Percent Change From Baseline in Triglycerides (TG)
    End point description
    Triglycerides (TG): percent (%) change from baseline by treatment over time = [TG at observation minus TG at Week 0] divided by TG at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). PD analysis population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 6, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    5
    10
    9
    15
    Units: percent change in TG
    arithmetic mean (standard deviation)
        Week 2
    5.66 ± 38.26
    -6.87 ± 29.08
    28.37 ± 85.32
    -0.56 ± 32.19
        Week 4
    -6.2 ± 32.55
    -21.43 ± 30.42
    1.27 ± 50.81
    -7.6 ± 25.75
        Week 6
    57.06 ± 78.73
    -1.27 ± 23.91
    -4.43 ± 32.52
    -2.72 ± 24.8
        Week 8
    1.69 ± 31.48
    -9.88 ± 33.31
    -20.94 ± 39.24
    -21.11 ± 23.85
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C)

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    End point title
    		 Absolute Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C)
    End point description
    Change from baseline in high-density lipoprotein cholesterol measured in millimoles per liter (mmol/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value. PD analysis population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 6, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    5
    10
    9
    15
    Units: mmol/L
    arithmetic mean (standard deviation)
        Baseline
    1.35 ± 0.12
    1.45 ± 0.29
    1.17 ± 0.18
    1.18 ± 0.23
        Week 2
    0.08 ± 0.24
    -0.1 ± 0.29
    -0.05 ± 0.26
    -0.01 ± 0.2
        Week 4
    -0.02 ± 0.05
    0 ± 0.19
    0.02 ± 0.21
    -0.01 ± 0.28
        Week 6
    -0.12 ± 0.29
    -0.01 ± 0.18
    0.04 ± 0.14
    -0.03 ± 0.23
        Week 8
    0.04 ± 0.22
    -0.07 ± 0.21
    0.08 ± 0.25
    -0.08 ± 0.22
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C)

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    End point title
    		 Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C)
    End point description
    High-density lipoprotein cholesterol (HDL-C): percent (%) change by treatment over time = [HDL-C at observation minus HDL-C at Week 0] divided by HDL-C at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). PD analysis population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 6, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    5
    10
    9
    15
    Units: percent change in HDL-C
    arithmetic mean (standard deviation)
        Week 2
    5.38 ± 17.32
    -6.45 ± 21.01
    -4.11 ± 19.96
    -0.77 ± 17.66
        Week 4
    -1.99 ± 3.9
    1.59 ± 13.18
    1.04 ± 17.38
    1.77 ± 23.22
        Week 6
    -10.18 ± 22.7
    -0.64 ± 10.35
    3.28 ± 11.63
    -2.78 ± 21.49
        Week 8
    2.5 ± 15.02
    -2.84 ± 14.49
    5.99 ± 21.02
    -5.19 ± 17.76
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Apolipoprotein A-1 (Apo A-1)

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    End point title
    		 Absolute Change From Baseline in Apolipoprotein A-1 (Apo A-1)
    End point description
    Change from baseline in Apolipoprotein A-1 measured in grams per liter (g/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value. PD analysis population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 6, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    5
    10
    9
    15
    Units: g/L
    arithmetic mean (standard deviation)
        Baseline
    1.42 ± 0.2
    1.45 ± 0.2
    1.29 ± 0.2
    1.24 ± 0.15
        Week 2
    0.01 ± 0.17
    -0.08 ± 0.23
    -0.09 ± 0.22
    -0.01 ± 0.15
        Week 4
    -0.09 ± 0.14
    -0.06 ± 0.13
    -0.06 ± 0.21
    0.07 ± 0.29
        Week 6
    -0.14 ± 0.18
    -0.02 ± 0.11
    -0.07 ± 0.19
    -0.04 ± 0.23
        Week 8
    -0.03 ± 0.12
    -0.05 ± 0.13
    -0.04 ± 0.24
    -0.07 ± 0.21
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1)

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    End point title
    		 Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1)
    End point description
    Apolipoprotein A-1 (Apo A-1): percent (%) change from baseline by treatment over time = [Apo A-1 at observation minus Apo A-1 at Week 0] divided by Apo A-1 at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). PD analysis population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 6, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    5
    10
    9
    15
    Units: percent change in Apo A-1
    arithmetic mean (standard deviation)
        Week 2
    1.69 ± 11.21
    -5.24 ± 15.86
    -5.96 ± 16.76
    -0.53 ± 11.9
        Week 4
    -5.15 ± 8.2
    -3.3 ± 8.11
    -3.73 ± 16.43
    7.54 ± 25.24
        Week 6
    -9.9 ± 14.01
    -0.97 ± 7.04
    -4.21 ± 14.81
    -2.82 ± 18.2
        Week 8
    -1.24 ± 8.49
    -3.37 ± 9.35
    -2.6 ± 20.22
    -4.82 ± 16.13
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Apolipoprotein B (Apo B)

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    End point title
    		 Absolute Change From Baseline in Apolipoprotein B (Apo B)
    End point description
    Change from baseline in Apolipoprotein B measured in grams per liter (g/L); assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]). Change from baseline = value at observation minus baseline value. PD analysis population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 6, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    5
    10
    9
    15
    Units: g/L
    arithmetic mean (standard deviation)
        Baseline
    1.09 ± 0.13
    1.49 ± 0.24
    1.26 ± 0.14
    1.52 ± 0.18
        Week 2
    -0.23 ± 0.13
    -0.31 ± 0.19
    -0.39 ± 0.14
    -0.42 ± 0.16
        Week 4
    -0.33 ± 0.11
    -0.4 ± 0.13
    -0.44 ± 0.1
    -0.47 ± 0.22
        Week 6
    -0.27 ± 0.15
    -0.53 ± 0.17
    -0.42 ± 0.15
    -0.52 ± 0.18
        Week 8
    -0.3 ± 0.08
    -0.59 ± 0.15
    -0.41 ± 0.17
    -0.49 ± 0.3
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Apolipoprotein B (Apo B)

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B (Apo B)
    End point description
    Apolipoprotein B (Apo B): percent (%) change from baseline by treatment over time = [Apo B at observation minus Apo B at Week 0] divided by Apo B at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 6, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    5
    10
    9
    15
    Units: percent change in Apo B
    arithmetic mean (standard deviation)
        Week 2
    -21.92 ± 13.97
    -19.88 ± 10.96
    -30.81 ± 10.27
    -27.46 ± 8.89
        Week 4
    -29.89 ± 8.94
    -26.56 ± 5.33
    -34.69 ± 6.1
    -30.42 ± 11.86
        Week 6
    -24.58 ± 12.96
    -35.26 ± 6.85
    -33.26 ± 10.38
    -33.61 ± 9.59
        Week 8
    -27.39 ± 5.97
    -39.59 ± 5.83
    -31.94 ± 11.64
    -31.26 ± 18.57
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C)

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    End point title
    		 Absolute Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C)
    End point description
    Change from baseline in very low-density lipoprotein-cholesterol (VLDL-C) measured in millimoles per liter (mmol/L). Change from baseline = value at observation minus baseline value. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 6, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    5
    10
    9
    15
    Units: mmol/L
    arithmetic mean (standard deviation)
        Baseline
    0.54 ± 0.15
    0.76 ± 0.3
    0.65 ± 0.11
    0.99 ± 0.31
        Change at Week 2
    -0.22 ± 0.12
    -0.31 ± 0.38
    -0.12 ± 0.29
    -0.38 ± 0.33
        Change at Week 4
    -0.18 ± 0.24
    -0.3 ± 0.27
    -0.14 ± 0.24
    -0.39 ± 0.35
        Change at Week 6
    -0.01 ± 0.17
    -0.28 ± 0.32
    -0.2 ± 0.17
    -0.36 ± 0.28
        Change at Week 8
    -0.13 ± 0.32
    -0.42 ± 0.28
    -0.35 ± 0.14
    -0.55 ± 0.32
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C)

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    End point title
    		 Percent Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C)
    End point description
    Very low-density lipoprotein-cholesterol (VLDL-C): percent (%) change from baseline by treatment over time = [VLDL-C at observation minus VLDL-C at Week 0] divided by VLDL-C at Week 0 * 100. Assessments were performed in the fasting state (minimum 10-hour fast [optional at Weeks 2 and 6]).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 6, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    5
    10
    9
    15
    Units: percent change in VLDL-C
    arithmetic mean (standard deviation)
        Week 2
    -42.2 ± 25.17
    -28.49 ± 43.5
    -14.5 ± 41.19
    -39.95 ± 37.24
        Week 4
    -30.66 ± 48.66
    -31.86 ± 37.62
    -21.1 ± 37.56
    -36.35 ± 28.79
        Week 6
    4.1 ± 36.46
    -25.59 ± 44.9
    -29.2 ± 25.11
    -35.08 ± 25.06
        Week 8
    -12.31 ± 57.38
    -50.29 ± 21.44
    -53.61 ± 19.21
    -52.38 ± 29.34
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Flow-Mediated Dilatation at Week 8

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    End point title
    		 Absolute Change From Baseline in Flow-Mediated Dilatation at Week 8
    End point description
    Brachial artery flow-mediated dilatation (FMD) = (max minus baseline diameter divided by baseline diameter) x 100%. Standardized image acquisition: brachial artery images recorded for one minute at rest, blood pressure cuff inflated to 250 mm Hg for 5 minutes with brachial artery imaged continuously throughout cuff inflation, cuff released to produce reactive hyperaemia and the brachial artery imaged continuously for 3 minutes after release. Total duration of measurement approximately 25 minutes. Change from baseline = value at observation minus baseline value. PD analysis population. Flow-mediated dilation (FMD) was measured at centers with established FMD facilities. PD analysis population. Flow-mediated dilation (FMD) was measured at centers with established FMD facilities.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    4
    7
    5
    12
    Units: FMD
    arithmetic mean (standard deviation)
        Baseline
    4.34 ± 3.15
    7.41 ± 3.3
    5.05 ± 3.86
    3.67 ± 2.51
        Change at Week 8
    -0.16 ± 2.32
    -1.14 ± 1.47
    -0.32 ± 4.83
    1.35 ± 2.73
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Flow-Mediated Dilatation at Week 8

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    End point title
    		 Percent Change From Baseline in Flow-Mediated Dilatation at Week 8
    End point description
    Brachial Flow-Mediated Dilatation (FMD) = (max minus baseline diameter divided by baseline diameter) x 100%.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    		 Stayed at 5 mg: Tanner Stage 1 Titrated to 10 mg: Tanner Stage 1 Stayed at 10 mg: Tanner Stage 2+ Titrated to 20 mg: Tanner Stage 2+
    Number of subjects analysed
    4
    7
    5
    12
    Units: percent change in FMD
        arithmetic mean (standard deviation)
    -17.19 ± 23.67
    -20.77 ± 37.03
    -9.77 ± 63.2
    1.49 ± 28.64
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 8
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    All Subjects (5 mg, 10 mg): Tanner Stage 1
    Reporting group description
    		 Atorvastatin: subjects who stayed at initial dose of 5 mg/day for duration of study and subjects who titrated after Week 4 to 10 mg/day if target LDL-C was not attained and study drug was well tolerated.

    Reporting group title
    All Subjects (10 mg, 20 mg): Tanner Stage 2+
    Reporting group description
    		 Atorvastatin: subjects who stayed at initial dose of 10 mg/day for duration of study and subjects who titrated to 20 mg/day after Week 4 if target LDL-C was not attained and study drug was well tolerated.

    Serious adverse events
    		 All Subjects (5 mg, 10 mg): Tanner Stage 1 All Subjects (10 mg, 20 mg): Tanner Stage 2+
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 24 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 All Subjects (5 mg, 10 mg): Tanner Stage 1 All Subjects (10 mg, 20 mg): Tanner Stage 2+
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 15 (60.00%)
    13 / 24 (54.17%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Blood creatinine increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 24 (4.17%)
         occurrences all number
    3
    1
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    Musculoskeletal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Gastritis viral
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Influenza
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 24 (8.33%)
         occurrences all number
    1
    2
    Tonsillitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Viral rhinitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    Hand fracture
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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