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    Clinical Trial Results:
    Modeling of the impact of a PCSK9 inhibition on lipoproteins in patients with dyslipidemia

    Summary
    EudraCT number
    		 2016-003551-30
    Trial protocol
    		 DE  
    Global end of trial date
    16 Jan 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 Feb 2021
    First version publication date
    16 Sep 2020
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction of the primary completition data

    Trial information

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    Trial identification
    Sponsor protocol code
    August2016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1192-0601
    Other trial identifiers
    		 DRKS: DRKS00011663
    Sponsors
    Sponsor organisation name
    Universitätsklinikum Freiburg Institut für klinische Chemie und Laboratoriumsmedizin
    Sponsor organisation address
    Hugstetter Str 55, Freiburg, Germany, 79106
    Public contact
    Karl Winkler, Universitätsklinikum Freiburg Institut für klinische Chemie und Laboratoriumsmedizin , 49 76127033160, karl.winkler@uniklinik-freiburg.de
    Scientific contact
    Karl Winkler, Universitätsklinikum Freiburg Institut für klinische Chemie und Laboratoriumsmedizin , 49 76127033160, karl.winkler@uniklinik-freiburg.de
    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
    16 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective is to study the impact of PCSK9 inhibitors in patients with dyslipidemia using a mathematical model describing the lipoproteins of low density (LDL)based on clinical data
    Protection of trial subjects
    Study was part of regular patient treatment. Hence Protection=regular protection in patient treatment
    Background therapy
    		 the protocol doesn't prescripe a background therapy
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    16
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Time-span of recruitment: 23.03.17 -01.12.18 All patients were recruited in the lipid ambulance of the university hospital Freiburg, Germany

    Pre-assignment
    Screening details
    		 no screening, patients of the lipid ambulance of the university hospital Freiburg, Germany, who fulfilled the inclusion criteria were included (given written consent)

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Praluent arm
    Arm description
    		 no PCSK9-inhibitor at baseline, start of PCSK9 inhibition thearpy directly after baseline-visit. visite 1 (~2 weeks after baseline-visit), visit 2 (~12 weeks after baseline visit)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Praluent
    Investigational medicinal product code
    EMA/504805/2015
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    75 mg every two weeks

    Arm title
    		 Repatha arm
    Arm description
    		 12 weeks Repatha
    Arm type
    		 Experimental

    Investigational medicinal product name
    Repatha
    Investigational medicinal product code
    EMEA/H/C/003766
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    140mg total every two weeks

    Number of subjects in period 1
    		Praluent arm Repatha arm
    Started
    15
    15
    Completed
    12
    12
    Not completed
    3
    3
         wrong administration
    1
    -
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 30 30
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 64 (50 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 15 15
        Male
    		 15 15

    End points

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    End points reporting groups
    Reporting group title
    Praluent arm
    Reporting group description
    		 no PCSK9-inhibitor at baseline, start of PCSK9 inhibition thearpy directly after baseline-visit. visite 1 (~2 weeks after baseline-visit), visit 2 (~12 weeks after baseline visit)

    Reporting group title
    Repatha arm
    Reporting group description
    		 12 weeks Repatha

    Primary: Estimation of the fractional catabolic rate (FCR) of Apolipoprotein B in LDL

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    End point title
    		 Estimation of the fractional catabolic rate (FCR) of Apolipoprotein B in LDL
    End point description
    This FCR is estimated using a mathematical model based on lipid-compositions of in the lipoproteinfractions VLDL, IDL, LDL and HDL. It results from the expected TG loss and the observed TG number per ApoB in LDL.
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 Praluent arm Repatha arm
    Number of subjects analysed
    13
    13
    Units: pools/day
    median (inter-quartile range (Q1-Q3))
        baseline
    0.0215 (0.0165 to 0.0358)
    0.0215 (0.0165 to 0.0358)
        2 weeks
    0.0455 (0.0224 to 0.0909)
    0.0455 (0.0224 to 0.0909)
        12 weeks
    0.0467 (0.0274 to 0.1074)
    0.0467 (0.0274 to 0.1074)
    Statistical analysis title
    		 FCR
    Statistical analysis description
    Change in FCR before (baseline) and after (12 weeks) treatment with PCSK9-inhibitor
    Comparison groups
    Repatha arm v Praluent arm
    Number of subjects included in analysis
    26
    Analysis specification
    Post-hoc
    Analysis type
    		 other [1]
    P-value
    		 = 0.000378 [2]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - Change in FCR before (baseline) and after (12 weeks) treatment with PCSK9-inhibitor Wilcoxon signed rank test
    [2] - The fractional catabolic rate (derived using a mathematical model) increases significantly due to therapy with PCSK9-inhibitors. This is in accordance with intuition

    Secondary: Cholesterol ester in HDL

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    End point title
    		 Cholesterol ester in HDL
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Praluent arm Repatha arm
    Number of subjects analysed
    13
    13
    Units: mg/dl
    median (inter-quartile range (Q1-Q3))
        baseline
    37.97 (32.1 to 47.1)
    41.1 (33 to 52.3)
        12 weeks
    38.2 (32.6 to 47.9)
    40.5 (31.7 to 51.7)
    No statistical analyses for this end point

    Secondary: TG in HDL

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    End point title
    		 TG in HDL
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Praluent arm Repatha arm
    Number of subjects analysed
    13
    13
    Units: mg/dl
    median (inter-quartile range (Q1-Q3))
        baseline
    10 (9 to 11)
    10 (8 to 13)
        12 weeks
    10 (9 to 11)
    11 (8 to 12)
    No statistical analyses for this end point

    Secondary: Cholesterol ester in LDL

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    End point title
    		 Cholesterol ester in LDL
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Praluent arm Repatha arm
    Number of subjects analysed
    13
    13
    Units: mg/dl
    median (inter-quartile range (Q1-Q3))
        baseline
    105 (82 to 113)
    109 (97 to 160)
        12 weeks
    50 (34 to 67)
    65 (31 to 81)
    No statistical analyses for this end point

    Secondary: Triglycerides in LDL

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    End point title
    		 Triglycerides in LDL
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Praluent arm Repatha arm
    Number of subjects analysed
    13
    13
    Units: mg/dl
    median (inter-quartile range (Q1-Q3))
        baseline
    22 (20 to 25)
    23 (20 to 33)
        12 weeks
    16 (10 to 18)
    17 (12 to 22)
    No statistical analyses for this end point

    Secondary: Cholesterol ester in VLDL

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    End point title
    		 Cholesterol ester in VLDL
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Praluent arm Repatha arm
    Number of subjects analysed
    13
    13
    Units: mg/dl
    median (inter-quartile range (Q1-Q3))
        baseline
    21 (9 to 30)
    19 (10 to 27)
        12 weeks
    12 (8 to 20)
    11 (8 to 17)
    No statistical analyses for this end point

    Secondary: Triglycerides in VLDL

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    End point title
    		 Triglycerides in VLDL
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Praluent arm Repatha arm
    Number of subjects analysed
    13
    13
    Units: mg/dl
    median (inter-quartile range (Q1-Q3))
        baseline
    96 (46 to 197)
    119 (48 to 126)
        12 weeks
    73 (54 to 136)
    71 (53 to 83)
    No statistical analyses for this end point

    Secondary: ApoB in LDL

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    End point title
    		 ApoB in LDL
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Praluent arm Repatha arm
    Number of subjects analysed
    13
    13
    Units: mg/dl
    median (inter-quartile range (Q1-Q3))
        baseline
    83 (72 to 98)
    95 (81 to 126)
        12 weeks
    47 (35 to 57)
    58 (30 to 73)
    No statistical analyses for this end point

    Secondary: ApoB in VLDL

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    End point title
    		 ApoB in VLDL
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Praluent arm Repatha arm
    Number of subjects analysed
    13
    13
    Units: mg/dl
    median (inter-quartile range (Q1-Q3))
        baseline
    14 (7 to 19)
    10 (7 to 15)
        12 weeks
    15 (8 to 19)
    9 (7 to 11)
    No statistical analyses for this end point

    Secondary: ApoA1 in HDL

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    End point title
    		 ApoA1 in HDL
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Praluent arm Repatha arm
    Number of subjects analysed
    13
    13
    Units: mg/dl
    median (inter-quartile range (Q1-Q3))
        baseline
    105 (93 to 113)
    112 (98 to 139)
        12 weeks
    107 (95 to 130)
    106 (93 to 146)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    overall arm
    Reporting group description
    		 no PCSK9-inhibitor at baseline, start of PCSK9 inhibition thearpy directly after baseline-visit. visite 1 (~2 weeks after baseline-visit), visit 2 (~12 weeks after baseline visit)

    Serious adverse events
    		 overall arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 overall arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 30 (13.33%)
    General disorders and administration site conditions
    Headache
         subjects affected / exposed [1]
    1 / 1 (100.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed [2]
    1 / 1 (100.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    itching, heat in the face
    alternative assessment type: Non-systematic
         subjects affected / exposed [3]
    1 / 1 (100.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    muscle pain, skin rash
         subjects affected / exposed [4]
    1 / 1 (100.00%)
         occurrences all number
    1
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: I have to admit, that I do not unterstand the warning (neither do I understand the difference between 'exposed' and 'affected'). However, there was only one case of that specific non-SAE in our study.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: I have to admit, that I do not unterstand the warning (neither do I understand the difference between 'exposed' and 'affected'). However, there was only one case of that specific non-SAE in our study.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: I have to admit, that I do not unterstand the warning (neither do I understand the difference between 'exposed' and 'affected'). However, there was only one case of that specific non-SAE in our study.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: I have to admit, that I do not unterstand the warning (neither do I understand the difference between 'exposed' and 'affected'). However, there was only one case of that specific non-SAE in our study.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30670016
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