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    Clinical Trial Results:
    A Double-Blind, Randomised, Placebo-Controlled, Parallel-Group, 12-Week Study of Pitavastatin in High-Risk Hyperlipidaemia in Childhood P/0230/2012, P/0231/2012, P/0232/2012 and P/0233/2012.

    Summary
    EudraCT number
    		 2011-004964-32
    Trial protocol
    		 NL   GR   FR   ES   NO   IT  
    Global end of trial date
    20 Mar 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Feb 2016
    First version publication date
    31 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NK-104-4.01EU
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Kowa Research Europe, Ltd
    Sponsor organisation address
    105 Wharfedale Road, Winnersh Triangle, Wokingham, United Kingdom, RG41 5RB
    Public contact
    Regulatory Affairs, Kowa Research Europe Co, Ltd., +44 (0)118 922 9000,
    Scientific contact
    Regulatory Affairs, Kowa Research Europe Co, Ltd., +44 (0)118 922 9000,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000300-PIP01-08 EMEA-000054-PIP01-07 EMEA-000302-PIP01-08 EMEA-000301-PIP01-08
    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 May 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Mar 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Mar 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the efficacy of pitavastatin 1 mg QD, 2 mg QD, and 4 mg QD to placebo in terms of the percentage reduction in LDL-C in children or adolescent patients with high-risk hyperlipidaemia at steady state (Week 12).
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. Each patient was assured of his/her right to withdraw from the study at any time. Close monitoring of all subjects was adhered to throughout the trial conduct. Patients were discouraged from starting any new medication without first consulting the Investigator, unless the new medication was required for emergency use. In general, any medication not excluded by the protocol was permitted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Apr 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
    Netherlands: 40
    Country: Number of subjects enrolled
    Norway: 15
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Greece: 22
    Country: Number of subjects enrolled
    Italy: 15
    Worldwide total number of subjects
    106
    EEA total number of subjects
    106
    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)
    67
    Adolescents (12-17 years)
    39
    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
    		 -

    Pre-assignment
    Screening details
    		 The study consisted of an up to 5-week screening/wash out period, and all participants were screened at specialist lipid clinics.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pitavastatin 1 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pitavastatin
    Investigational medicinal product code
    NK-104
    Other name
    PITAVASTATIN CALCIUM
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Pitavastatin 1 mg was to be taken orally, once daily in the morning. Duration of treatment is 12 weeks.

    Arm title
    		 Pitavastatin 2 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pitavastatin
    Investigational medicinal product code
    NK-104
    Other name
    PITAVASTATIN CALCIUM
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Pitavastatin 2 mg was to be taken orally, once daily in the morning. Duration of treatment is 12 weeks.

    Arm title
    		 Pitavastatin 4 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pitavastatin
    Investigational medicinal product code
    NK-104
    Other name
    PITAVASTATIN CALCIUM
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Pitavastatin was to be taken orally, once daily in the morning. Pitavastatin 2 mg was received for the first 4 weeks and then pitavastatin 4 mg for the remaining 8 weeks of the treatment period.

    Arm title
    		 Placebo group
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was to be taken orally, once daily in the morning. Duration of treatment is 12 weeks.

    Number of subjects in period 1
    		Pitavastatin 1 mg Pitavastatin 2 mg Pitavastatin 4 mg Placebo group
    Started
    26
    27
    26
    27
    Completed
    26
    26
    24
    27
    Not completed
    0
    1
    2
    0
         Consent withdrawn by subject
    -
    -
    1
    -
         Adverse event, non-fatal
    -
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pitavastatin 1 mg
    Reporting group description
    		 -

    Reporting group title
    Pitavastatin 2 mg
    Reporting group description
    		 -

    Reporting group title
    Pitavastatin 4 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo group
    Reporting group description
    		 -

    Reporting group values
    		 Pitavastatin 1 mg Pitavastatin 2 mg Pitavastatin 4 mg Placebo group Total
    Number of subjects
    		 26 27 26 27 106
    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)
    		 15 15 17 20 67
        Adolescents (12-17 years)
    		 11 12 9 7 39
        Adults (18-64 years)
    		 0 0 0 0 0
        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)
    		 10.5 ± 2.75 11.1 ± 2.87 10.3 ± 2.66 10.4 ± 3.26 -
    Gender categorical
    Units: Subjects
        Female
    		 14 17 12 15 58
        Male
    		 12 10 14 12 48

    End points

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    End points reporting groups
    Reporting group title
    Pitavastatin 1 mg
    Reporting group description
    		 -

    Reporting group title
    Pitavastatin 2 mg
    Reporting group description
    		 -

    Reporting group title
    Pitavastatin 4 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo group
    Reporting group description
    		 -

    Subject analysis set title
    Pitavastatin 1 mg vs. Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set was defined as all randomized patients who received at least 1 dose of study drug and had a valid baseline lipid measurement and at least 1 valid post-baseline lipid measurement.

    Subject analysis set title
    Pitavastatin 2 mg vs. Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set was defined as all randomized patients who received at least 1 dose of study drug and had a valid baseline lipid measurement and at least 1 valid post-baseline lipid measurement.

    Subject analysis set title
    Pitavastatin 4 mg vs. Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set was defined as all randomized patients who received at least 1 dose of study drug and had a valid baseline lipid measurement and at least 1 valid post-baseline lipid measurement.

    Primary: The primary efficacy endpoint of this study was the percent change in LDL-C from baseline to Week 12 with LOCF

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    End point title
    		 The primary efficacy endpoint of this study was the percent change in LDL-C from baseline to Week 12 with LOCF
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to Week 12
    End point values
    		 Pitavastatin 1 mg Pitavastatin 2 mg Pitavastatin 4 mg Placebo group
    Number of subjects analysed
    26
    26
    24
    27
    Units: percent change in LDL-C
        least squares mean (standard error)
    -23.5 ± 2.09
    -30.1 ± 2.11
    -39.3 ± 2.18
    1 ± 2.06
    Statistical analysis title
    		 Pitavastatin 1 mg vs. Placebo
    Comparison groups
    Pitavastatin 1 mg v Placebo group
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -24.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.3
         upper limit
    		 -18.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.94
    Statistical analysis title
    		 Pitavastatin 2 mg vs. Placebo
    Comparison groups
    Pitavastatin 2 mg v Placebo group
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -31.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37
         upper limit
    		 -25.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.96
    Statistical analysis title
    		 Pitavastatin 4 mg vs. Placebo
    Comparison groups
    Pitavastatin 4 mg v Placebo group
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -40.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -46.2
         upper limit
    		 -34.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.99

    Secondary: Percent change in LDL-C from baseline over 12 weeks of treatment

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    End point title
    		 Percent change in LDL-C from baseline over 12 weeks of treatment
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline over 12 weeks of treatment (Week 4, Week 8, and Week 12)
    End point values
    		 Pitavastatin 1 mg Pitavastatin 2 mg Pitavastatin 4 mg Placebo group
    Number of subjects analysed
    26
    26
    24
    27
    Units: Percent change in LDL-C
    number (not applicable)
        Percent change in week 4
    -24.1
    -31.1
    -28.7
    0.5
        Percent change in week 8
    -24.2
    -20.7
    -39.5
    -1.5
        Percent change in week 12
    -23.3
    -29.7
    -40.3
    1.3
    No statistical analyses for this end point

    Secondary: Percentages of patients who achieved American Heart Association minimal (130 mg/dL [3.4 mmol/L]) and ideal (110 mg/dL [2.8 mmol/L]) LDL-C targets

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    End point title
    		 Percentages of patients who achieved American Heart Association minimal (130 mg/dL [3.4 mmol/L]) and ideal (110 mg/dL [2.8 mmol/L]) LDL-C targets
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to week 12 with LOCF
    End point values
    		 Pitavastatin 1 mg Pitavastatin 2 mg Pitavastatin 4 mg Placebo group
    Number of subjects analysed
    26
    26
    24
    27
    Units: Percentages of patients
    number (not applicable)
        LDL-C <130 mg/dL
    3.8
    30.8
    37.5
    0
        LDL-C <110 mg/dL
    0
    7.7
    16.7
    0
    No statistical analyses for this end point

    Secondary: Percent changes in HDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), TG, apolipoprotein A1 (Apo A1), and apolipoprotein B (Apo B)

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    End point title
    		 Percent changes in HDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), TG, apolipoprotein A1 (Apo A1), and apolipoprotein B (Apo B)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to week 12 with LOCF
    End point values
    		 Pitavastatin 1 mg Pitavastatin 2 mg Pitavastatin 4 mg Placebo group
    Number of subjects analysed
    26
    26
    24
    27
    Units: Percent change
    least squares mean (standard error)
        HDL-C
    6.1 ± 2.5
    -2.4 ± 2.52
    -3.1 ± 2.61
    1.1 ± 2.46
        non-HDL
    -22.9 ± 2.14
    -28.5 ± 2.15
    -37.2 ± 2.23
    1.1 ± 2.1
        TC
    -17.8 ± 1.78
    -24.2 ± 1.79
    -31.3 ± 1.86
    0.9 ± 1.75
        TG
    -7.6 ± 6.26
    -5.9 ± 6.43
    0.3 ± 6.6
    2 ± 6.15
        Apo A1
    1.1 ± 2.16
    -3.6 ± 2.16
    -2.2 ± 2.24
    -0.8 ± 2.12
        Apo B
    -21.6 ± 2.24
    -25 ± 2.25
    -28.8 ± 2.33
    0.4 ± 2.2
    No statistical analyses for this end point

    Secondary: Changes in TC:HDL-C ratio, non-HDL-C:HDL-C ratio, and Apo B:Apo A1 ratio

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    End point title
    		 Changes in TC:HDL-C ratio, non-HDL-C:HDL-C ratio, and Apo B:Apo A1 ratio
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to week 12 with LOCF
    End point values
    		 Pitavastatin 1 mg Pitavastatin 2 mg Pitavastatin 4 mg Placebo group
    Number of subjects analysed
    26
    26
    24
    27
    Units: Ratio
    least squares mean (standard error)
        TC:HDL-C ratio
    -1.36 ± 0.151
    -1.32 ± 0.152
    -1.73 ± 0.157
    -0.04 ± 0.148
        non-HDL-C:HDL-C ratio
    -1.36 ± 0.151
    -1.32 ± 0.152
    -1.73 ± 0.157
    -0.04 ± 0.148
        Apo B:Apo A1 ratio
    -0.25 ± 0.032
    -0.24 ± 0.032
    -0.3 ± 0.033
    0 ± 0.031
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The evaluation of safety during the double-blind period was based primarily on the frequency of adverse events, SAEs, discontinuations due to adverse events, clinical laboratory assessments etc.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Pitavastatin 1 mg
    Reporting group description
    		 -

    Reporting group title
    Pitavastatin 2 mg
    Reporting group description
    		 -

    Reporting group title
    Pitavastatin 4 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Pitavastatin 1 mg Pitavastatin 2 mg Pitavastatin 4 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Pitavastatin 1 mg Pitavastatin 2 mg Pitavastatin 4 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 26 (69.23%)
    16 / 27 (59.26%)
    11 / 26 (42.31%)
    15 / 27 (55.56%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 26 (23.08%)
    5 / 27 (18.52%)
    1 / 26 (3.85%)
    2 / 27 (7.41%)
         occurrences all number
    7
    7
    1
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 26 (11.54%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    3
    3
    0
    3
    Abdominal discomfort
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    3 / 27 (11.11%)
         occurrences all number
    1
    0
    1
    3
    Vomiting
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
    3 / 27 (11.11%)
         occurrences all number
    0
    0
    1
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 26 (15.38%)
    6 / 27 (22.22%)
    2 / 26 (7.69%)
    6 / 27 (22.22%)
         occurrences all number
    4
    6
    2
    6
    Influenza
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    3
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    0

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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