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    Clinical Trial Results:
    Phase III, single-arm, open-label, international, multi-centre study to evaluate the efficacy and safety of lomitapide in paediatric patients with Homozygous Familial Hypercholesterolaemia (HoFH) on stable lipid-lowering therapy

    Summary
    EudraCT number
    		 2019-002278-30
    Trial protocol
    		 DE   IT  
    Global end of trial date
    06 Jun 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Dec 2024
    First version publication date
    21 Dec 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    APH-19
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04681170
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amryt Pharmaceuticals DAC
    Sponsor organisation address
    45 Mespil Road, Dublin 4, Ireland,
    Public contact
    Head of Clinical Operations, Amryt Pharmaceuticals DAC, 353 15180200, janet.boylan@amrytpharma.com
    Scientific contact
    Head of Clinical Operations, Amryt Pharmaceuticals DAC, 353 15180200, janet.boylan@amrytpharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001124-PIP01-10
    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
    02 Jul 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Jun 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jun 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of lomitapide as defined by the percent change in low-density lipoprotein cholesterol (LDL-C) at the maximum tolerated dose (MTD) at Week 24±3 days (W24) compared to baseline when added to stable lipid-lowering therapy (LLT, including lipoprotein apheresis [LA] where applicable) in paediatric patients (5 to ≤17 years of age) with HoFH.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and with Good Clinical Practice (GCP) guidelines as denoted in the International Conference on Harmonization (ICH) E6 requirements. These practices included IRB/IEC procedures, informed consent, protocol adherence, administrative documents, drug supply accountability, data collection, patient records (source documents), adverse event (AE) recording and reporting, inspection and audit preparation, and record retention. The Investigator was made aware that regulatory authorities and representatives of the Sponsor could inspect the documents and patient records at any time. All subject identities were kept confidential. Each subject was assigned a unique subject number, which in turn was used in the electronic case report form (eCRF) instead of the subject’s name.
    Background therapy
    		 All subjects were required to complete a Run in Period of a minimum of 6 weeks. During the Run in period, subjects were stabilised on their current LLT (including LA, if applicable). Each subject was to remain on their stable LLT regimen (including LA, if applicable) during the 24 week Efficacy Phase. After 24 weeks, adjustments to background LLT (including LA, if applicable) were allowed for optimal standard of care at the discretion of the Investigator.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    14 Dec 2020
    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
    Saudi Arabia: 15
    Country: Number of subjects enrolled
    Tunisia: 7
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Italy: 7
    Worldwide total number of subjects
    46
    EEA total number of subjects
    21
    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)
    21
    Adolescents (12-17 years)
    25
    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
    		 Male and female subjects aged 5 to ≤17 years with HoFH were enrolled in the trial at 12 study centres in various countries (3 in Germany, 1 in Israel, 2 in Italy, 2 in Saudi Arabia, 3 in Spain and 1 in Tunisia). The first patient first visit was 14 Dec 2020 and the last patient last visit was 06 Jun 2024.

    Pre-assignment
    Screening details
    		 Subjects underwent assessments to determine eligibility at the Initial Screening Visit (up to 12 weeks prior to Day 0). A total of 46 subjects were enrolled in this study. Of these, 3 subjects were ‘Run in’ failures and did not complete the Run in Period.). Therefore, a total of 43 (93.5%) subjects entered the Efficacy Phase at Visit 4.

    Period 1
    Period 1 title
    Pre-run in
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All patients from all age groups
    Arm description
    		 -
    Arm type
    		 Main arm - screening phase - no IMP administrated

    Investigational medicinal product name
    Lomitapide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    In the screening phase no IMP has been administered.

    Number of subjects in period 1
    		All patients from all age groups
    Started
    46
    Completed
    46
    Period 2
    Period 2 title
    Stratified enrolment & run-in
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All age groups
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		All age groups
    Started
    46
    Completed
    43
    Not completed
    3
         Consent withdrawn by subject
    1
         Death due to a non-treatment emergent AE
    1
         Protocol deviation
    1
    Period 3
    Period 3 title
    Open label efficacy phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 5-10 years
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lomitapide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lomitapide capsules were provided in 4 dose strengths of 2 mg, 5 mg, 10 mg, and 20 mg and were administered orally once daily. After stabilization of each subject on his/her current MTD of LLT (including LA, if applicable) during the 6 week Run in Period, treatment with lomitapide was started as add on therapy on Day 0 of the Efficacy Phase. The dose was initiated at the recommended starting dose for the subject’s age and escalated to the maximum dose applicable to their age as shown below based upon safety and tolerability in addition to LDL C values: - 5-10 years old subjects: Starting dose 2 mg/day; MTD 20 mg/day

    Arm title
    		 11-17 years
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lomitapide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lomitapide capsules were provided in 4 dose strengths of 2 mg, 5 mg, 10 mg, and 20 mg and were administered orally once daily. After stabilization of each subject on his/her current MTD of LLT (including LA, if applicable) during the 6 week Run in Period, treatment with lomitapide was started as add on therapy on Day 0 of the Efficacy Phase. The dose was initiated at the recommended starting dose for the subject’s age and escalated to the maximum dose applicable to their age as shown below based upon safety and tolerability in addition to LDL C values: - 11-15 years old subjects: Starting dose 2 mg/day; MTD 40 mg/day - 16-17 years old subjects: Starting dose 5 mg/day; MTD 60 mg/day

    Arm title
    		 All age groups
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lomitapide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lomitapide capsules were provided in 4 dose strengths of 2 mg, 5 mg, 10 mg, and 20 mg and were administered orally once daily. After stabilization of each subject on his/her current MTD of LLT (including LA, if applicable) during the 6 week Run in Period, treatment with lomitapide was started as add on therapy on Day 0 of the Efficacy Phase. The dose was initiated at the recommended starting dose for the subject’s age and escalated to the maximum dose applicable to their age as shown below based upon safety and tolerability in addition to LDL C values: - 5-10 years old subjects: Starting dose 2 mg/day; MTD 20 mg/day - 11-15 years old subjects: Starting dose 2 mg/day; MTD 40 mg/day - 16-17 years old subjects: Starting dose 5 mg/day; MTD 60 mg/day

    Number of subjects in period 3
    		5-10 years 11-17 years All age groups
    Started
    20
    23
    43
    Completed
    20
    21
    41
    Not completed
    0
    2
    2
         Adverse event, non-fatal
    -
    2
    2
    Period 4
    Period 4 title
    Open label safety phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 All age groups
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lomitapide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Each subject was to continue to receive their MTD of lomitapide achieved during the Efficacy Phase (unless criteria were met for reducing or increasing the dose) for an additional 80±1 weeks in the Safety Phase (for a total treatment period of 2 years).

    Arm title
    		 5-10 years
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lomitapide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Each subject was to continue to receive their MTD of lomitapide achieved during the Efficacy Phase (unless criteria were met for reducing or increasing the dose) for an additional 80±1 weeks in the Safety Phase (for a total treatment period of 2 years).

    Arm title
    		 11-17 years
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lomitapide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Each subject was to continue to receive their MTD of lomitapide achieved during the Efficacy Phase (unless criteria were met for reducing or increasing the dose) for an additional 80±1 weeks in the Safety Phase (for a total treatment period of 2 years).

    Number of subjects in period 4
    		All age groups 5-10 years 11-17 years
    Started
    41
    20
    21
    Completed
    39
    20
    19
    Not completed
    2
    0
    2
         Consent withdrawn by subject
    1
    -
    1
         AEs and none compliance
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pre-run in
    Reporting group description
    		 -

    Reporting group values
    		 Pre-run in Total
    Number of subjects
    		 46 46
    Age categorical
    Units: Subjects
        5-10 years
    		 21 21
        11-17 years
    		 25 25
    Gender categorical
    Units: Subjects
        Female
    		 25 25
        Male
    		 21 21

    End points

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    End points reporting groups
    Reporting group title
    All patients from all age groups
    Reporting group description
    		 -
    Reporting group title
    All age groups
    Reporting group description
    		 -
    Reporting group title
    5-10 years
    Reporting group description
    		 -

    Reporting group title
    11-17 years
    Reporting group description
    		 -

    Reporting group title
    All age groups
    Reporting group description
    		 -
    Reporting group title
    All age groups
    Reporting group description
    		 -

    Reporting group title
    5-10 years
    Reporting group description
    		 -

    Reporting group title
    11-17 years
    Reporting group description
    		 -

    Primary: LDL-C at Baseline and Week 24/LOCF

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    End point title
    		 LDL-C at Baseline and Week 24/LOCF [1]
    End point description
    End point type
    Primary
    End point timeframe
    Percent change from Baseline in LDL-C at Week 24±3 days.
    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: This was a single-arm study, no comparative group can be assigned; the comparison made is done only between baseline and Week 24. Analysis was made using the one-sample t-test to test the null hypothesis that the percentage change from Baseline was equal to zero against the alternative hypothesis that the percentage change from Baseline was not equal to zero.
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline
    435.791 ( 189.4620 )
        Week 24/LOCF
    175.404 ( 89.8979 )
        Change from Baseline
    -260.386 ( 192.1284 )
        Percent Change from Baseline
    -53.910 ( 25.8287 )
    Attachments
    		 Waterfall Plot of Percentage Change from Baseline
    No statistical analyses for this end point

    Secondary: Percent Change in non-HDL-C from Baseline at Week 24/LOCF

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    End point title
    		 Percent Change in non-HDL-C from Baseline at Week 24/LOCF
    End point description
    Analysis was made using the one-sample t-test to test the null hypothesis that the percentage change from Baseline was equal to zero against the alternative hypothesis that the percentage change from Baseline was not equal to zero.
    End point type
    Secondary
    End point timeframe
    Percent change from Baseline at Week 24±3 days for the lipid parameter non-HDL-C
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: mg/dL
    arithmetic mean (standard deviation)
        Observed Value
    183.632 ( 92.0566 )
        Change from Baseline
    -270.493 ( 194.7326 )
        Percent Change from Baseline
    -54.185 ( 25.0256 )
    No statistical analyses for this end point

    Secondary: Percent Change in TC from Baseline at Week 24/LOCF

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    End point title
    		 Percent Change in TC from Baseline at Week 24/LOCF
    End point description
    Analysis was made using the one-sample t-test to test the null hypothesis that the percentage change from Baseline was equal to zero against the alternative hypothesis that the percentage change from Baseline was not equal to zero.
    End point type
    Secondary
    End point timeframe
    Percent change from Baseline at Week 24±3 days for the lipid parameter TC
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: mg/dL
    arithmetic mean (standard deviation)
        Observed Value
    216.866 ( 94.1528 )
        Change from Baseline
    -268.668 ( 194.2576 )
        Percent Change from Baseline
    -50.176 ( 24.5397 )
    No statistical analyses for this end point

    Secondary: Percent Change in VLDL-C from Baseline at Week 24/LOCF

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    End point title
    		 Percent Change in VLDL-C from Baseline at Week 24/LOCF
    End point description
    Analysis was made using the one-sample t-test to test the null hypothesis that the percentage change from Baseline was equal to zero against the alternative hypothesis that the percentage change from Baseline was not equal to zero.
    End point type
    Secondary
    End point timeframe
    Percent change from Baseline at Week 24±3 days for the lipid parameter VLDL-C
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: mg/dL
    arithmetic mean (standard deviation)
        Observed Value
    8.344 ( 4.7206 )
        Change from Baseline
    -9.981 ( 8.1272 )
        Percent Change from Baseline
    -49.678 ( 31.6126 )
    No statistical analyses for this end point

    Secondary: Percent Change in Apo B from Baseline at Week 24/LOCF

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    End point title
    		 Percent Change in Apo B from Baseline at Week 24/LOCF
    End point description
    Analysis was made using the one-sample t-test to test the null hypothesis that the percentage change from Baseline was equal to zero against the alternative hypothesis that the percentage change from Baseline was not equal to zero.
    End point type
    Secondary
    End point timeframe
    Percent change from Baseline at Week 24±3 days for the lipid parameter Apo B
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: mg/dL
    arithmetic mean (standard deviation)
        Observed Value
    131.3 ( 62.59 )
        Change from Baseline
    -185.3 ( 130.66 )
        Percent Change from Baseline
    -53.1 ( 24.76 )
    No statistical analyses for this end point

    Secondary: Percent Change in Triglycerides from Baseline at Week 24/LOCF

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    End point title
    		 Percent Change in Triglycerides from Baseline at Week 24/LOCF
    End point description
    Analysis was made using the one-sample t-test to test the null hypothesis that the percentage change from Baseline was equal to zero against the alternative hypothesis that the percentage change from Baseline was not equal to zero.
    End point type
    Secondary
    End point timeframe
    Percent change from Baseline at Week 24±3 days for the lipid parameter Triglycerides
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: mg/dL
    arithmetic mean (standard deviation)
        Observed Value
    42.068 ( 23.1235 )
        Change from Baseline
    -49.828 ( 40.4354 )
        Percent Change from Baseline
    -49.28 ( 31.7290 )
    No statistical analyses for this end point

    Secondary: Percent Change in Lipid Parameter Lp(a) from Baseline at Week 24/LOCF

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    End point title
    		 Percent Change in Lipid Parameter Lp(a) from Baseline at Week 24/LOCF
    End point description
    Analysis was made using the one-sample t-test to test the null hypothesis that the percentage change from Baseline was equal to zero against the alternative hypothesis that the percentage change from Baseline was not equal to zero.
    End point type
    Secondary
    End point timeframe
    Percent change from Baseline at Week 24±3 days for the lipid parameter Lp(a)
    End point values
    		 All age groups
    Number of subjects analysed
    28
    Units: nmol/L
    arithmetic mean (standard deviation)
        Observed Value
    82.493 ( 75.5080 )
        Change from Baseline
    -47.383 ( 59.2811 )
        Percent Change from Baseline
    -26.757 ( 32.5675 )
    Attachments
    		 Change in Lp(a) (mg/dL vs. nmol/L)
    No statistical analyses for this end point

    Secondary: Percent Change in LDL-C from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)

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    End point title
    		 Percent Change in LDL-C from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline at All Other Time Points to Week 104 (refer also to the below-listed results covering the safety phase)
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: %
    arithmetic mean (standard deviation)
        Week 4
    -1.962 ( 20.7168 )
        Week 8
    -6.798 ( 19.1524 )
        Week 12
    -16.638 ( 23.1978 )
        Week 16
    -36.458 ( 17.9894 )
        Week 20
    -50.730 ( 24.8321 )
        Week 24
    -54.602 ( 26.4557 )
    No statistical analyses for this end point

    Secondary: Percent Change in LDL-C from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)

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    End point title
    		 Percent Change in LDL-C from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline at All Other Time Points to Week 104 (refer also to the above-listed results covering the efficacy phase)
    End point values
    		 All age groups
    Number of subjects analysed
    41
    Units: %
    arithmetic mean (standard deviation)
        Week 28
    -55.518 ( 28.5714 )
        Week 32
    -52.126 ( 28.7496 )
        Week 36
    -39.823 ( 32.6612 )
        Week 40
    -49.427 ( 29.5830 )
        Week 44
    -44.312 ( 30.3775 )
        Week 48
    -45.315 ( 29.6526 )
        Week 52
    -44.583 ( 32.8128 )
        Week 56
    -45.994 ( 34.3631 )
        Week 68
    -40.831 ( 37.3821 )
        Week 80
    -42.319 ( 34.9400 )
        Week 92
    -37.199 ( 39.6625 )
        Week 104
    -40.159 ( 30.5026 )
    No statistical analyses for this end point

    Secondary: Percent Change in non-HDL-C from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)

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    End point title
    		 Percent Change in non-HDL-C from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in non-HDL-C from Baseline at All Other Time Points to Week 104 (refer also to the below-listed results covering the safety phase)
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: %
    arithmetic mean (standard deviation)
        Week 4
    -1.765 ( 21.1682 )
        Week 8
    -6.745 ( 18.6776 )
        Week 12
    -16.497 ( 22.9850 )
        Week 16
    -36.610 ( 17.4339 )
        Week 20
    -50.928 ( 24.3958 )
        Week 24
    -55.033 ( 25.4297 )
    No statistical analyses for this end point

    Secondary: Percent Change in non-HDL-C from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)

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    End point title
    		 Percent Change in non-HDL-C from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in non-HDL-C from Baseline at All Other Time Points to Week 104 (refer also to the below-listed results covering the efficacy phase)
    End point values
    		 All age groups
    Number of subjects analysed
    41
    Units: %
    arithmetic mean (standard deviation)
        Week 28
    -55.984 ( 27.5559 )
        Week 32
    -52.629 ( 27.8748 )
        Week 36
    -40.574 ( 31.4293 )
        Week 40
    -50.013 ( 28.4878 )
        Week 44
    -44.702 ( 29.8885 )
        Week 48
    -46.770 ( 29.3974 )
        Week 52
    -45.222 ( 31.9577 )
        Week 56
    -46.558 ( 33.4734 )
        Week 68
    -41.576 ( 36.0854 )
        Week 80
    -42.388 ( 34.3439 )
        Week 92
    -37.755 ( 38.4243 )
        Week 104
    -40.511 ( 30.1102 )
    No statistical analyses for this end point

    Secondary: Percent Change in TC from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)

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    End point title
    		 Percent Change in TC from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in TC from Baseline at All Other Time Points to Week 104 (refer also to the below-listed results covering the safety phase)
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: %
    arithmetic mean (standard deviation)
        Week 4
    -2.057 ( 19.3772 )
        Week 8
    -6.970 ( 17.6904 )
        Week 12
    -15.961 ( 21.4313 )
        Week 16
    -33.976 ( 15.7159 )
        Week 20
    -48.177 ( 23.2987 )
        Week 24
    -50.922 ( 24.9738 )
    No statistical analyses for this end point

    Secondary: Percent Change in TC from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)

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    End point title
    		 Percent Change in TC from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in TC from Baseline at All Other Time Points to Week 104 (refer also to the above-listed results covering the efficacy phase)
    End point values
    		 All age groups
    Number of subjects analysed
    41
    Units: %
    arithmetic mean (standard deviation)
        Week 28
    -51.998 ( 26.9668 )
        Week 32
    -48.945 ( 26.2375 )
        Week 36
    -40.643 ( 30.5125 )
        Week 40
    -45.402 ( 27.5358 )
        Week 44
    -41.443 ( 28.3745 )
        Week 48
    -44.164 ( 27.6987 )
        Week 52
    -42.764 ( 30.6617 )
        Week 56
    -43.234 ( 31.3599 )
        Week 68
    -39.672 ( 33.2025 )
        Week 80
    -40.291 ( 31.9119 )
        Week 92
    -34.946 ( 35.8485 )
        Week 104
    -36.017 ( 32.2354 )
    No statistical analyses for this end point

    Secondary: Percent Change in VLDL-C from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)

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    End point title
    		 Percent Change in VLDL-C from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in VLDL-C from Baseline at All Other Time Points to Week 104 (refer also to the below-listed results covering the safety phase)
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: %
    arithmetic mean (standard deviation)
        Week 4
    9.770 ( 42.2029 )
        Week 8
    2.857 ( 34.5887 )
        Week 12
    -7.405 ( 48.8428 )
        Week 16
    -34.706 ( 31.6590 )
        Week 20
    -49.068 ( 25.6958 )
        Week 24
    -53.050 ( 27.2118 )
    No statistical analyses for this end point

    Secondary: Percent Change in VLDL-C from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)

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    End point title
    		 Percent Change in VLDL-C from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in VLDL-C from Baseline at All Other Time Points to Week 104 (refer also to the above-listed results covering the efficacy phase)
    End point values
    		 All age groups
    Number of subjects analysed
    41
    Units: %
    arithmetic mean (standard deviation)
        Week 28
    -55.394 ( 25.0601 )
        Week 32
    -47.899 ( 55.7396 )
        Week 36
    -46.596 ( 25.9994 )
        Week 40
    -51.167 ( 26.7498 )
        Week 44
    -46.750 ( 33.3163 )
        Week 48
    -38.148 ( 50.6100 )
        Week 52
    -49.469 ( 30.0996 )
        Week 56
    -47.051 ( 32.7429 )
        Week 68
    -47.832 ( 30.6844 )
        Week 80
    -36.881 ( 44.5589 )
        Week 92
    -41.368 ( 31.7375 )
        Week 104
    -39.055 ( 40.2422 )
    No statistical analyses for this end point

    Secondary: Percent Change in apo B from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)

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    End point title
    		 Percent Change in apo B from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in apo B from Baseline at All Other Time Points to Week 104 (refer also to the below-listed results covering the safety phase)
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: %
    arithmetic mean (standard deviation)
        Week 4
    0.2 ( 18.99 )
        Week 8
    -6.5 ( 19.25 )
        Week 12
    -15.5 ( 21.91 )
        Week 16
    -36.1 ( 16.70 )
        Week 20
    -51.6 ( 24.21 )
        Week 24
    -54.0 ( 25.02 )
    No statistical analyses for this end point

    Secondary: Percent Change in apo B from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)

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    End point title
    		 Percent Change in apo B from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in apo B from Baseline at All Other Time Points to Week 104 (refer also to the above-listed results covering the efficacy phase)
    End point values
    		 All age groups
    Number of subjects analysed
    41
    Units: %
    arithmetic mean (standard deviation)
        Week 28
    -56.2 ( 26.17 )
        Week 32
    -52.0 ( 28.64 )
        Week 36
    -43.9 ( 30.91 )
        Week 40
    -48.9 ( 29.11 )
        Week 44
    -46.1 ( 28.75 )
        Week 48
    -48.6 ( 29.03 )
        Week 52
    -47.7 ( 30.16 )
        Week 56
    -47.1 ( 33.06 )
        Week 68
    -44.8 ( 33.99 )
        Week 80
    -47.1 ( 30.58 )
        Week 92
    -41.8 ( 35.12 )
        Week 104
    -44.6 ( 30.22 )
    No statistical analyses for this end point

    Secondary: Percent Change in triglycerides from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)

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    End point title
    		 Percent Change in triglycerides from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in triglycerides from Baseline at All Other Time Points to Week 104 (refer also to the below-listed results covering the safety phase)
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: %
    arithmetic mean (standard deviation)
        Week 4
    9.387 ( 41.7233 )
        Week 8
    2.649 ( 35.3115 )
        Week 12
    -7.258 ( 49.6990 )
        Week 16
    -34.970 ( 30.2259 )
        Week 20
    -48.989 ( 25.8872 )
        Week 24
    -52.878 ( 26.8475 )
    No statistical analyses for this end point

    Secondary: Percent Change in triglycerides from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)

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    End point title
    		 Percent Change in triglycerides from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in triglycerides from Baseline at All Other Time Points to Week 104 (refer also to the above-listed results covering the efficacy phase)
    End point values
    		 All age groups
    Number of subjects analysed
    41
    Units: %
    arithmetic mean (standard deviation)
        Week 28
    -55.639 ( 24.6317 )
        Week 32
    -48.697 ( 54.0396 )
        Week 36
    -46.823 ( 25.4762 )
        Week 40
    -51.612 ( 25.9533 )
        Week 44
    -47.065 ( 31.7596 )
        Week 48
    -39.769 ( 48.3307 )
        Week 52
    -49.415 ( 28.4096 )
        Week 56
    -47.707 ( 32.0150 )
        Week 68
    -48.471 ( 30.8061 )
        Week 80
    -38.312 ( 44.1074 )
        Week 92
    -41.549 ( 30.2027 )
        Week 104
    -39.739 ( 39.8597 )
    No statistical analyses for this end point

    Secondary: Percent Change in LP(a) from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)

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    End point title
    		 Percent Change in LP(a) from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in LP(a) from Baseline at All Other Time Points to Week 104 (refer also to the below-listed results covering the safety phase)
    End point values
    		 All age groups
    Number of subjects analysed
    28
    Units: %
    arithmetic mean (standard deviation)
        Week 4
    9.660 ( 63.5768 )
        Week 8
    1.508 ( 46.1156 )
        Week 12
    0.592 ( 32.5241 )
        Week 16
    -14.648 ( 26.3140 )
        Week 20
    -16.602 ( 47.9856 )
        Week 24
    -28.874 ( 33.5277 )
    No statistical analyses for this end point

    Secondary: Percent Change in LP(a) from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)

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    End point title
    		 Percent Change in LP(a) from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in LP(a) from Baseline at All Other Time Points to Week 104 (refer also to the above-listed results covering the efficacy phase)
    End point values
    		 All age groups
    Number of subjects analysed
    28
    Units: %
    arithmetic mean (standard deviation)
        Week 28
    -32.628 ( 32.4047 )
        Week 32
    -20.594 ( 50.1160 )
        Week 36
    -25.278 ( 32.4201 )
        Week 40
    -28.257 ( 34.6849 )
        Week 44
    -30.124 ( 34.9943 )
        Week 48
    -17.905 ( 38.3429 )
        Week 52
    -25.635 ( 42.3832 )
        Week 56
    -22.366 ( 34.5809 )
        Week 68
    -20.634 ( 42.9257 )
        Week 80
    -22.659 ( 42.2271 )
        Week 92
    -22.235 ( 41.1508 )
        Week 104
    -29.064 ( 34.5930 )
    No statistical analyses for this end point

    Secondary: Percent Change in TC/HDL-C ratio from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)

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    End point title
    		 Percent Change in TC/HDL-C ratio from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in TC/HDL-C ratio from Baseline at All Other Time Points to Week 104 (refer also to the below-listed results covering the safety phase)
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: %
    arithmetic mean (standard deviation)
        Week 4
    0.108 ( 27.5756 )
        Week 8
    -5.292 ( 29.1737 )
        Week 12
    -14.501 ( 27.7248 )
        Week 16
    -33.384 ( 25.8765 )
        Week 20
    -45.689 ( 27.0372 )
        Week 24
    -52.155 ( 25.1906 )
    No statistical analyses for this end point

    Secondary: Percent Change in TC/HDL-C ratio from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)

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    End point title
    		 Percent Change in TC/HDL-C ratio from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in TC/HDL-C ratio from Baseline at All Other Time Points to Week 104 (refer also to the above-listed results covering the efficacy phase)
    End point values
    		 All age groups
    Number of subjects analysed
    41
    Units: %
    arithmetic mean (standard deviation)
        Week 28
    -50.986 ( 31.0715 )
        Week 32
    -48.651 ( 35.4572 )
        Week 36
    -35.860 ( 35.4801 )
        Week 40
    -43.976 ( 36.8573 )
        Week 44
    -40.395 ( 38.1876 )
        Week 48
    -41.720 ( 36.2674 )
        Week 52
    -43.496 ( 38.2302 )
        Week 56
    -39.188 ( 55.5616 )
        Week 68
    -36.874 ( 41.9020 )
        Week 80
    -39.189 ( 37.9268 )
        Week 92
    -37.274 ( 41.0451 )
        Week 104
    -39.358 ( 34.3438 )
    No statistical analyses for this end point

    Secondary: Percent Change in HDL-C ratio from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)

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    End point title
    		 Percent Change in HDL-C ratio from Baseline at All Other Time Points to Week 104 (efficacy phase results from Baseline to Week 24)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in HDL-C ratio from Baseline at All Other Time Points to Week 104 (refer also to the below-listed results covering the safety phase)
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: %
    arithmetic mean (standard deviation)
        Week 4
    1.428 ( 19.6280 )
        Week 8
    4.482 ( 26.0635 )
        Week 12
    4.912 ( 29.1215 )
        Week 16
    8.059 ( 31.4604 )
        Week 20
    6.186 ( 33.3664 )
        Week 24
    11.412 ( 33.0044 )
    No statistical analyses for this end point

    Secondary: Percent Change in HDL-C ratio from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)

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    End point title
    		 Percent Change in HDL-C ratio from Baseline at All Other Time Points to Week 104 (safety phase results from Week 28 to Week 104)
    End point description
    End point type
    Secondary
    End point timeframe
    Percent Change in HDL-C ratio from Baseline at All Other Time Points to Week 104 (refer also to the above-listed results covering the efficacy phase)
    End point values
    		 All age groups
    Number of subjects analysed
    41
    Units: %
    arithmetic mean (standard deviation)
        Week 28
    11.154 ( 36.3133 )
        Week 32
    15.137 ( 33.9304 )
        Week 36
    8.537 ( 30.2218 )
        Week 40
    10.043 ( 35.0097 )
        Week 44
    12.765 ( 33.2136 )
        Week 48
    13.602 ( 37.5732 )
        Week 52
    18.032 ( 35.1079 )
        Week 56
    11.528 ( 29.1750 )
        Week 68
    9.557 ( 30.6616 )
        Week 80
    11.606 ( 30.8242 )
        Week 92
    17.320 ( 33.0024 )
        Week 104
    16.109 ( 37.2987 )
    No statistical analyses for this end point

    Secondary: Change in LLT from Week 28 through Week 104

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    End point title
    		 Change in LLT from Week 28 through Week 104
    End point description
    End point type
    Secondary
    End point timeframe
    Week 28 through Week 104
    End point values
    		 All age groups
    Number of subjects analysed
    41
    Units: Number of patients
        Reduction due to low LDL-C
    2
        Discontinuation due to lomitapide increase
    1
        Discontinuation due to other reason
    2
        Increase due to high LDL-C
    3
        Increase due to other reason
    1
    No statistical analyses for this end point

    Secondary: Change in LA from Week 28 through Week 104

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    End point title
    		 Change in LA from Week 28 through Week 104
    End point description
    End point type
    Secondary
    End point timeframe
    Week 28 through Week 104
    End point values
    		 All age groups
    Number of subjects analysed
    17
    Units: Number of patients
        Reduction due to AE
    1
        Reduction due to low LDL-C
    3
        Reduction due to other reason
    4
        Discontinuation due to low LDL-C
    1
        Discontinuation due to other reason
    1
    No statistical analyses for this end point

    Secondary: Percentage of Patients Achieving EAS Recommended Target (2013) of LDL-C at any timepoint between Baseline and Week 24

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    End point title
    		 Percentage of Patients Achieving EAS Recommended Target (2013) of LDL-C at any timepoint between Baseline and Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    Anytime up to Week 24
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: Percentage of patients
        <135 mg/dL - anytime up to Week 24
    42
        <115 mg/dL - anytime up to Week 24
    37
        <110 mg/dL - anytime up to Week 24
    33
    No statistical analyses for this end point

    Secondary: Percentage of Patients Achieving EAS Recommended Target (2013) of LDL-C at any time in the study

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    End point title
    		 Percentage of Patients Achieving EAS Recommended Target (2013) of LDL-C at any time in the study
    End point description
    End point type
    Secondary
    End point timeframe
    Anytime in the study
    End point values
    		 All age groups
    Number of subjects analysed
    41
    Units: Percentage of patients
        <135 mg/dL - anytime up to week 104
    54
        <115 mg/dL - anytime up to week 104
    57
        <110 mg/dL - anytime up to week 104
    44
    No statistical analyses for this end point

    Other pre-specified: Percent change of BMI (efficacy phase results from Baseline to Week 24)

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    End point title
    		 Percent change of BMI (efficacy phase results from Baseline to Week 24)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 104 (refer also to the data presented in the table below for the safety phase)
    End point values
    		 All age groups
    Number of subjects analysed
    43
    Units: %
    arithmetic mean (standard deviation)
        Week 4
    -1.06 ( 3.466 )
        Week 8
    -1.32 ( 3.954 )
        Week 12
    -2.36 ( 4.768 )
        Week 16
    -2.96 ( 5.288 )
        Week 20
    -4.21 ( 5.708 )
        Week 24
    -5.04 ( 5.997 )
    No statistical analyses for this end point

    Other pre-specified: Percent change of BMI (safety phase results from Week 28 to Week 104)

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    End point title
    		 Percent change of BMI (safety phase results from Week 28 to Week 104)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 104 (refer also to the data presented in the table above for the efficacy phase)
    End point values
    		 All age groups
    Number of subjects analysed
    41
    Units: %
    arithmetic mean (standard deviation)
        Week 28
    -4.13 ( 6.427 )
        Week 32
    -3.60 ( 7.145 )
        Week 36
    -3.92 ( 7.949 )
        Week 40
    -3.78 ( 8.293 )
        Week 44
    -3.71 ( 10.406 )
        Week 48
    -3.92 ( 10.420 )
        Week 52
    -3.21 ( 10.738 )
        Week 56
    -2.90 ( 11.520 )
        Week 68
    -3.00 ( 12.103 )
        Week 80
    -1.90 ( 12.665 )
        Week 92
    -1.00 ( 14.108 )
        Week 104
    -0.11 ( 13.718 )
    No statistical analyses for this end point

    Other pre-specified: Lipid Accumulation in the Liver Over Time - NMR (efficacy phase results from Baseline to Week 24)

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    End point title
    		 Lipid Accumulation in the Liver Over Time - NMR (efficacy phase results from Baseline to Week 24)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From Baseline to Week 104/EoT. Please refer also to the data below for data from the safety phase.
    End point values
    		 5-10 years 11-17 years
    Number of subjects analysed
    4
    19
    Units: Number of patients
        Baseline - ≤10% liver fat
    2
    16
        Baseline - >10% and ≤20% liver fat
    0
    1
        Baseline - >20% liver fat
    0
    0
        Week 24 - ≤10% liver fat
    1
    12
        Week 24 - >10% and ≤20% liver fat
    1
    2
        Week 24 - >20% liver fat
    0
    1
        Week 24 - No result
    2
    4
    No statistical analyses for this end point

    Other pre-specified: Lipid Accumulation in the Liver Over Time - NMR (safety phase results from Week 28 to Week 104)

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    End point title
    		 Lipid Accumulation in the Liver Over Time - NMR (safety phase results from Week 28 to Week 104)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From Baseline to Week 104/EoT. Please refer also to the data above for data from the efficacy phase.
    End point values
    		 5-10 years 11-17 years
    Number of subjects analysed
    4
    19
    Units: Number of patients
        Week 56 - ≤10% liver fat
    0
    9
        Week 56 - >10% and ≤20% liver fat
    1
    4
        Week 56 - >20% liver fat
    0
    0
        Week 56 - No result
    2
    5
        Week 104/EoT - ≤10% liver fat
    3
    11
        Week 104/EoT - >10% and ≤20% liver fat
    1
    4
        Week 104/EoT - >20% liver fat
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Lipid Accumulation in the Liver Over Time - Ultrasound (efficacy phase results from Baseline to Week 24)

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    End point title
    		 Lipid Accumulation in the Liver Over Time - Ultrasound (efficacy phase results from Baseline to Week 24)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From Baseline to Week 104/EoT. Please refer also to the data below for data from the safety phase.
    End point values
    		 5-10 years 11-17 years
    Number of subjects analysed
    17
    2
    Units: Number of patients
        Baseline - ≤10% liver fat
    17
    2
        Baseline - >10% and ≤20% liver fat
    0
    0
        Baseline - >20% liver fat
    0
    0
        Week 24 - ≤10% liver fat
    15
    2
        Week 24 - >10% and ≤20% liver fat
    0
    0
        Week 24 - >20% liver fat
    0
    0
        Week 24 - No result
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Lipid Accumulation in the Liver Over Time - Ultrasound (safety phase results from Week 28 to Week 104)

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    End point title
    		 Lipid Accumulation in the Liver Over Time - Ultrasound (safety phase results from Week 28 to Week 104)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From Baseline to Week 104/EoT. Please refer also to the data above for data from the efficacy phase.
    End point values
    		 5-10 years 11-17 years
    Number of subjects analysed
    17
    2
    Units: Number of patients
        Week 56 - ≤10% liver fat
    15
    2
        Week 56 - >10% and ≤20% liver fat
    1
    0
        Week 56 - >20% liver fat
    0
    0
        Week 56 - No result
    0
    0
        Week 104/EoT - ≤10% liver fat
    15
    0
        Week 104/EoT - >10% and ≤20% liver
    0
    1
        Week 104/EoT - >20% liver fat
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were monitored throughout the study from the time of informed consent through Week 108.
    Adverse event reporting additional description
    Safety variables included evaluations of AEs, laboratory test results (including assessment of bone health), vital signs, ECGs, pulmonary function tests, and imaging of the liver. In addition, available standard of care echocardiography results were reviewed.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    		 All patients from all age groups from the time of informed consent through Week 108.

    Serious adverse events
    		 All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 43 (25.58%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Investigations
    Transaminases increased
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Shunt occlusion
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Aortic arteriosclerosis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Aortic valve disease mixed
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Vascular device occlusion
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Tendon disorder
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Vascular device infection
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 43 (97.67%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    17 / 43 (39.53%)
         occurrences all number
    28
    Aspartate aminotransferase increased
         subjects affected / exposed
    15 / 43 (34.88%)
         occurrences all number
    28
    Blood creatine phosphokinase increased
         subjects affected / exposed
    6 / 43 (13.95%)
         occurrences all number
    6
    C-reactive protein increased
         subjects affected / exposed
    6 / 43 (13.95%)
         occurrences all number
    8
    ECG signs of ventricular hypertrophy
         subjects affected / exposed
    5 / 43 (11.63%)
         occurrences all number
    5
    Transaminases increased
         subjects affected / exposed
    5 / 43 (11.63%)
         occurrences all number
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    8
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    14 / 43 (32.56%)
         occurrences all number
    21
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 43 (18.60%)
         occurrences all number
    12
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    22 / 43 (51.16%)
         occurrences all number
    44
    Abdominal pain
         subjects affected / exposed
    19 / 43 (44.19%)
         occurrences all number
    59
    Vomiting
         subjects affected / exposed
    12 / 43 (27.91%)
         occurrences all number
    26
    Abdominal pain upper
         subjects affected / exposed
    5 / 43 (11.63%)
         occurrences all number
    9
    Nausea
         subjects affected / exposed
    5 / 43 (11.63%)
         occurrences all number
    6
    Flatulence
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 43 (16.28%)
         occurrences all number
    9
    Oropharyngeal pain
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    6
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    6
    Xanthoma
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    4
    Infections and infestations
    COVID-19
         subjects affected / exposed
    9 / 43 (20.93%)
         occurrences all number
    12
    Nasopharyngitis
         subjects affected / exposed
    6 / 43 (13.95%)
         occurrences all number
    12
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    6
    Gastroenteritis
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Pharyngitis
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 43 (13.95%)
         occurrences all number
    8
    Vitamin D deficiency
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    4
    Abnormal loss of weight
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Aug 2019
    Amendment 1.0: - Inconsistencies between the timing of assessments in the study flowchart and the visit descriptions corrected. - Assessment of bone health as a secondary objective clarified. - Genetic testing procedure clarified. - Description of palatability assessments included.
    04 Dec 2019
    Amendment 2.0 (first version of protocol approved in Germany): - Change of exclusion criterion 12 to avoid overlapping toxicities. - Amendment of exclusion criterion 14 to exclude breastfeeding subjects from the study. - Change of subject discontinuation criteria to obligatory permanently discontinue treatment in subjects meeting Hy’s law case criteria or showing any comparable signs of liver toxicity, irrespective of origin. - Implementation of recruitment stop and individual benefit risk assessment for further administration of study medication in case a subject must discontinue treatment due to Hy’s law or comparable signs of liver toxicity.
    14 Feb 2020
    Amendment 3.0 (Amendment 1.0 in Germany): - Long-term extension phase of study added instead of named patient supply of lomitapide. - Permission to down-titrate to intermediate doses at Investigator’s discretion added. - Central laboratory measurements of fat-soluble vitamin levels and EFAs added. - Central genetic testing added and clarified that genetic testing was to be strongly encouraged but not mandated. - Exploratory sub-study (Liposcale® Test) using aliquots of PK samples added. - Screening laboratory tests for HBsAg and hepatitis C antibody deleted. - Inconsistencies between study flowchart and visit schedule for serum lipase corrected. - Address for SAE reporting updated. - Inconsistencies in safety follow-up and safety reporting details corrected. - Parameters to be measured during pulmonary function tests clarified. - Procedure for weighing subjects clarified. - Study design figure simplified. - Updated to allow local sourcing of dietary supplements. - List of participating countries revised.
    04 Sep 2020
    Amendment 4.0: - Inconsistencies in safety follow-up and safety reporting details corrected in Amendment 3.0 reverted (at request of BfArM, Germany). - Use of MRI or ultrasound for measurement of lipid accumulation in the liver clarified. - Rationale for dose selection updated. - Assessment of vital signs at every visit and inclusion of ECGs every 3 to 6 months added. - Collection of standard-of-care echocardiography data/results when available added. - Contraceptive measures section updated. - Re-screening process clarified. - Measurement of ‘Holman Index’ i.e., ratio of eicosatrienoic acid to arachidonic acid removed. - Sponsor address updated.
    21 Sep 2020
    Amendment 4.1: - Inconsistency in flowchart footnotes corrected.
    17 Nov 2020
    Amendment 4.2 (implemented in Germany only): - Re-screening details updated (at request of BfArM, Germany).
    05 May 2022
    Amendment 5.0: - Inconsistencies between objectives and endpoints corrected. - Updated to allow dose increase after Week 24. - Statistical methods clarified: - Clarified methodology of primary efficacy analysis and added timing of the primary efficacy analysis and final analysis. - Specified the use of 2-side significance level at 5% for primary and secondary efficacy parameters. - Updated definition of study population to clarify that safety analysis set included subjects with least one dose of the study medication, FAS included subjects with at least one post-Baseline measurement of LDL-C and completers analysis set included subjects not discontinued at the end of efficacy phase. - Analysis of primary efficacy endpoint was updated to specify the use of one sample t test to test the primary efficacy endpoint, clarified that imputation of missing data using LOCF only applies to Efficacy Phase and when a Baseline value is not missing, added sensitivity analyses using a MMRM, supplementary analyses based on per-protocol and completers analysis sets and subgroup analyses. - Addition of visit windows to handle time window violations for lipid data analyses. - Addition of exploratory and palatability endpoints. - Use of PER Registry for subjects who became pregnant during the study removed.
    09 Feb 2023
    Amendment 6.0: - Updated to remove reference to long-term extension study and include options to enter an EAP for subjects <18 years of age or to transition to commercial product for subjects ≥18 years of age. - References to EMA SmPC updated to Lojuxta® SPC in lieu of an Investigator’s Brochure. - Updated to remove PK analysis of lomitapide metabolites.

    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.
    Lp(a) analysis was analysed locally as central analysis was only available from January 2022.
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