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    Clinical Trial Results:
    An Open Label Multicenter Extension Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of SBC-102 in Adult Subjects with Liver Dysfunction Due to Lysosomal Acid Lipase Deficiency Who Previously Received Treatment in Study LAL-CL01

    Summary
    EudraCT number
    2011-001513-13
    Trial protocol
    GB   CZ  
    Global end of trial date
    21 Jun 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    04 Jan 2019
    First version publication date
    08 Jul 2018
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    No new data was added. Per EMA service desk, a new version was created to fix a technical issue with the version number of the results.

    Trial information

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    Trial identification
    Sponsor protocol code
    LAL-CL04
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01488097
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals
    Sponsor organisation address
    100 College Street, New Haven, CT, United States, 06510
    Public contact
    Alexion Pharmaceuticals, Alexion Pharmaceuticals, 001 7814302497, clinicaltrials@alexion.com
    Scientific contact
    Alexion Pharmaceuticals, Alexion Pharmaceuticals, 001 7814302497, clinicaltrials@alexion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the long-term safety and tolerability of sebelipase alfa in participants with liver dysfunction due to Lysosomal Acid Lipase (LAL) Deficiency.
    Protection of trial subjects
    This study was conducted according to applicable Good Clinical Practice regulations and International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines, as well as relevant institutional research policies and procedures and according to ethical principles that have their origin in the Declaration of Helsinki. All participants in this study were provided a consent form describing the study and providing sufficient information for participants to make an informed decision about their participation in the study. This consent form was submitted with the protocol for review and approval by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for the study. The formal consent of the participant, using the IRB/IEC-approved consent form, was obtained before that participant underwent any study procedure.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Dec 2011
    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
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 3
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    France: 1
    Worldwide total number of subjects
    8
    EEA total number of subjects
    4
    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)
    8
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants who successfully received all 4 doses of sebelipase alfa in Study LAL-CL01 and opted to continue treatment in the extension study underwent screening assessments to determine study eligibility. Eligible participants initiated treatment in the extension study at least 4 weeks after their last dose of sebelipase alfa in Study LAL-CL01.

    Pre-assignment
    Screening details
    9 participants who completed Study LAL-CL01 (received all 4 doses of sebelipase alfa) were screened for eligibility for enrollment in this extension study (LAL-CL04). 8 participants met all enrollment criteria and were enrolled. 1 participant who required a liver transplant no longer met the entry criteria.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    This is an open-label study.

    Arms
    Arm title
    Open-Label Sebelipase Alfa
    Arm description
    Participants were administered sebelipase alfa once weekly (qw) as an intravenous (IV) infusion at the same dose received in Study LAL-CL01 (0.35, 1, or 3 milligrams per kilogram [mg/kg]) for 4 weeks. After the initial 4 qw doses, participants transitioned to dosing every other week (qow) at either 1 mg/kg (participants who initiated treatment at 0.35 or 1 mg/kg qw) or 3 mg/kg (participants who initiated dosing at 3 mg/kg qw). Subsequent modifications to the dose and dosing frequency were permitted for individual participants based on observed safety, tolerability, and clinical response to treatment. Participants could continue to receive treatment with sebelipase alfa for up to 5 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Sebelipase Alfa
    Investigational medicinal product code
    SBC-102
    Other name
    Kanuma®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV infusions of sebelipase alfa at 0.35, 1, or 3 mg/kg administered qw for 4 weeks and IV infusions of sebelipase alfa at 1 or 3 mg/kg administered qow for up to 5 years.

    Number of subjects in period 1
    Open-Label Sebelipase Alfa
    Started
    8
    Received Study Drug in Extension Study
    8
    Completed
    7
    Not completed
    1
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    All participants who received any amount of study drug in the extension study.

    Reporting group values
    Overall Trial Total
    Number of subjects
    8 8
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    8 8
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    30.3 ± 10.69 -
    Gender categorical
    Units: Subjects
        Female
    2 2
        Male
    6 6
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0
        Asian
    0 0
        Native Hawaiian or Other Pacific Islander
    0 0
        Black or African American
    0 0
        White
    8 8
        More than one race
    0 0
        Unknown or Not Reported
    0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0 0
        Not Hispanic or Latino
    8 8
        Unknown or not reported
    0 0

    End points

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    End points reporting groups
    Reporting group title
    Open-Label Sebelipase Alfa
    Reporting group description
    Participants were administered sebelipase alfa once weekly (qw) as an intravenous (IV) infusion at the same dose received in Study LAL-CL01 (0.35, 1, or 3 milligrams per kilogram [mg/kg]) for 4 weeks. After the initial 4 qw doses, participants transitioned to dosing every other week (qow) at either 1 mg/kg (participants who initiated treatment at 0.35 or 1 mg/kg qw) or 3 mg/kg (participants who initiated dosing at 3 mg/kg qw). Subsequent modifications to the dose and dosing frequency were permitted for individual participants based on observed safety, tolerability, and clinical response to treatment. Participants could continue to receive treatment with sebelipase alfa for up to 5 years.

    Subject analysis set title
    Sebelipase Alfa 1 mg/kg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants were administered sebelipase alfa qw as an IV infusion at the same dose received in Study LAL-CL01 (0.35, 1, or 3 mg/kg) for 4 weeks. After the initial 4 qw doses, participants transitioned to dosing qow at 1 mg/kg (participants who initiated treatment at 0.35 or 1 mg/kg qw). Subsequent modifications to the dose and dosing frequency were permitted for individual participants based on observed safety, tolerability, and clinical response to treatment. Participants could continue to receive treatment with sebelipase alfa for up to 5 years.

    Subject analysis set title
    Sebelipase Alfa 3 mg/kg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants were administered sebelipase alfa qw as an IV infusion at the same dose received in Study LAL-CL01 (0.35, 1, or 3 mg/kg) for 4 weeks. After the initial 4 qw doses, participants transitioned to dosing qow at 3 mg/kg (participants who initiated dosing at 3 mg/kg qw). Subsequent modifications to the dose and dosing frequency were permitted for individual participants based on observed safety, tolerability, and clinical response to treatment. Participants could continue to receive treatment with sebelipase alfa for up to 5 years.

    Primary: Number Of Participants Reporting TEAEs And IARs

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    End point title
    Number Of Participants Reporting TEAEs And IARs [1]
    End point description
    Safety and tolerability of sebelipase alfa was primarily assessed by monitoring the number of participants reporting treatment-emergent adverse events (TEAEs), including serious adverse events, and infusion-associated reactions (IARs). The number of participants who discontinued from the study due to a TEAE is also presented. An IAR was defined as any adverse event that occurred during the 2-hour (hr) infusion or within 4 hrs after the end of the infusion and was assessed by the investigator as at least possibly related to study drug. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. TEAEs that occurred after the first dose administration at Week 1 through the End of Study (EOS) are presented. End of study was 30 days (+ 7 days) after the last dose of study drug (at Week 260).
    End point type
    Primary
    End point timeframe
    From after first dose administration post-Baseline through EOS during study LAL-CL04
    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: No statistical hypothesis testing was planned for this primary endpoint.
    End point values
    Open-Label Sebelipase Alfa
    Number of subjects analysed
    8
    Units: Count of Participants
        TEAEs
    8
        Serious TEAEs
    1
        IARs
    2
        TEAEs Leading to Study Discontinuation
    0
    No statistical analyses for this end point

    Secondary: Changes From Baseline In ALT And AST

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    End point title
    Changes From Baseline In ALT And AST
    End point description
    Changes from Baseline to Week 12, Week 24, Week 52, Week 104, Week 156, Week 208, Week 260, and EOS for alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Baseline values were defined as the last measurement prior to the first infusion of sebelipase alfa in Study LAL-CL04. The analysis population includes participants in the Full Analysis Set (FAS) for whom ALT and AST data were available at both Baseline and the indicated post-treatment time point. The FAS included all participants who received at least 1 complete infusion of sebelipase alfa in this study and who had at least 1 post-treatment measurement in this study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 52, Week 104, Week 156, Week 208, Week 260, and EOS
    End point values
    Open-Label Sebelipase Alfa
    Number of subjects analysed
    8
    Units: units (U)/liter (L)
    arithmetic mean (standard deviation)
        ALT Week 12 (n=8)
    -35.9 ± 19.99
        ALT Week 24 (n=8)
    -38.1 ± 24.00
        ALT Week 52 (n=7)
    -40.6 ± 20.50
        ALT Week 104 (n=8)
    -42.5 ± 19.65
        ALT Week 156 (n=8)
    -29.5 ± 20.38
        ALT Week 208 (n=7)
    -26.7 ± 30.58
        ALT Week 260 (n=5)
    -31.6 ± 21.78
        ALT EOS (n=7)
    -26.6 ± 31.10
        AST Week 12 (n=8)
    -13.9 ± 7.02
        AST Week 24 (n=8)
    -12.4 ± 11.71
        AST Week 52 (n=7)
    -18.6 ± 12.82
        AST Week 104 (n=8)
    -11.8 ± 15.59
        AST Week 156 (n=8)
    -12.8 ± 9.95
        AST Week 208 (n=7)
    -10.4 ± 14.86
        AST Week 260 (n=5)
    -10.8 ± 13.70
        AST EOS (n=5)
    -15.3 ± 14.27
    No statistical analyses for this end point

    Secondary: Changes From Baseline In Liver Volume

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    End point title
    Changes From Baseline In Liver Volume
    End point description
    Changes in liver volume from Baseline to Week 10 or 12, Week 24, Week 52, Week 104, Week 156, Week 208, Week 260, and EOS was assessed by magnetic resonance imaging (MRI). Baseline values were defined as the last measurement prior to the first infusion of sebelipase alfa in Study LAL-CL04. Liver volume was expressed as multiples of normal (MN), where normal is defined as 2.5% of body weight. The analysis population includes participants in the FAS for whom liver volume data were available at both Baseline and the indicated post-treatment time point. The FAS included all participants who received at least 1 complete infusion of sebelipase alfa in this study and who had at least 1 post-treatment measurement in this study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 10 or 12, Week 24, Week 52, Week 104, Week 156, Week 208, Week 260, and EOS
    End point values
    Open-Label Sebelipase Alfa
    Number of subjects analysed
    8
    Units: Multiples of Normal (MN)
    arithmetic mean (standard deviation)
        Week 10 or 12 (n=8)
    -0.096 ± 0.0892
        Week 24 (n=8)
    -0.099 ± 0.1513
        Week 52 (n=7)
    -0.096 ± 0.0641
        Week 104 (n=7)
    -0.176 ± 0.0801
        Week 156 (n=5)
    -0.082 ± 0.0732
        Week 208 (n=5)
    -0.182 ± 0.0556
        Week 260 (n=2)
    -0.218 ± 0.0388
        EOS (n=2)
    -0.205 ± 0.0358
    No statistical analyses for this end point

    Secondary: Changes From Baseline In Liver Fat Content

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    End point title
    Changes From Baseline In Liver Fat Content
    End point description
    Changes in liver fat content from Baseline to Week 10 or 12, Week 24, Week 52, Week 104, Week 156, Week 208, and Week 260, as assessed by multi-echo gradient-echo MRI. Baseline values were defined as the last measurement prior to the first infusion of sebelipase alfa in Study LAL-CL04. The analysis population includes participants in the FAS for whom liver fat content data were available at both Baseline and the indicated post-treatment time point. The FAS included all participants who received at least 1 complete infusion of sebelipase alfa in this study and who had at least 1 post-treatment measurement in this study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 10 or 12, Week 24, Week 52, Week 104, Week 156, Week 208, and Week 260
    End point values
    Open-Label Sebelipase Alfa
    Number of subjects analysed
    8
    Units: Percentage fat fraction
    arithmetic mean (standard deviation)
        Week 10 or 12 (n=5)
    -2.816 ± 1.8025
        Week 24 (n=5)
    -2.772 ± 3.0024
        Week 52 (n=4)
    -3.633 ± 2.5736
        Week 104 (n=4)
    -4.348 ± 2.4486
        Week 156 (n=4)
    -3.953 ± 4.1182
        Week 208 (n=3)
    -4.007 ± 3.4260
        Week 260 (n=2)
    -0.060 ± 3.4507
    No statistical analyses for this end point

    Secondary: Changes From Baseline In GGT And ALP

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    End point title
    Changes From Baseline In GGT And ALP
    End point description
    Changes from Baseline to Week 12, Week 24, Week 52, Week 104, Week 156, Week 208, Week 260, and EOS for gamma glutamyltransferase (GGT) and alkaline phosphatase (ALP). Baseline values were defined as the last measurement prior to the first infusion of sebelipase alfa in Study LAL-CL04. The analysis population includes participants in the FAS for whom GGT and ALP data were available at both Baseline and the indicated post-treatment time point. The FAS included all participants who received at least 1 complete infusion of sebelipase alfa in this study and who had at least 1 post-treatment measurement in this study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 52, Week 104, Week 156, Week 208, Week 260, and EOS
    End point values
    Open-Label Sebelipase Alfa
    Number of subjects analysed
    8
    Units: U/L
    arithmetic mean (standard deviation)
        GGT Week 12 (n=8)
    -13.6 ± 28.79
        GGT Week 24 (n=8)
    -13.8 ± 24.63
        GGT Week 52 (n=7)
    -14.0 ± 18.89
        GGT Week 104 (n=8)
    -22.4 ± 34.01
        GGT Week 156 (n=8)
    0.1 ± 11.32
        GGT Week 208 (n=7)
    2.3 ± 10.13
        GGT Week 260 (n=5)
    -6.0 ± 12.33
        GGT EOS (n=7)
    -4.0 ± 7.70
        ALP Week 12 (n=8)
    -15.3 ± 12.09
        ALP Week 24 (n=8)
    -18.3 ± 20.74
        ALP Week 52 (n=7)
    -12.4 ± 18.78
        ALP Week 104 (n=8)
    -18.0 ± 9.68
        ALP Week 156 (n=8)
    -6.4 ± 11.81
        ALP Week 208 (n=7)
    -5.9 ± 16.60
        ALP Week 260 (n=5)
    -14.2 ± 21.32
        ALP EOS (n=7)
    -7.9 ± 20.82
    No statistical analyses for this end point

    Secondary: Changes From Baseline In Serum Lipids

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    End point title
    Changes From Baseline In Serum Lipids
    End point description
    Lipid changes from Baseline to Week 10 or 12, Week 24, Week 52, Week 104, Week 156, Week 208, Week 260, and EOS were measured in serum for total cholesterol (Total-C), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), and triglycerides (TG). Baseline values were defined as the last measurement prior to the first infusion of sebelipase alfa in Study LAL-CL04. The analysis population includes participants in the FAS for whom lipid data were available at both Baseline and the indicated post-treatment time point. The FAS included all participants who received at least 1 complete infusion of sebelipase alfa in this study and who had at least 1 post-treatment measurement in this study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 10 or 12, Week 24, Week 52, Week 104, Week 156, Week 208, Week 260, and EOS
    End point values
    Open-Label Sebelipase Alfa
    Number of subjects analysed
    8
    Units: mg/dL
    arithmetic mean (standard deviation)
        Total-C Week 12 (n=8)
    -34.5 ± 40.50
        Total-C Week 24 (n=8)
    -59.3 ± 38.83
        Total-C Week 52 (n=7)
    -73.9 ± 54.43
        Total-C Week 104 (n=8)
    -60.8 ± 50.82
        Total-C Week 156 (n=8)
    -36.4 ± 43.90
        Total-C Week 208 (n=7)
    1.1 ± 93.21
        Total-C Week 260 (n=5)
    -45.5 ± 50.85
        Total-C EOS (n=7)
    -21.9 ± 59.89
        HDL-C Week 12 (n=8)
    4.9 ± 3.95
        HDL-C Week 24 (n=8)
    5.7 ± 6.19
        HDL-C Week 52 (n=7)
    9.0 ± 7.25
        HDL-C Week 104 (n=8)
    6.5 ± 9.04
        HDL-C Week 156 (n=8)
    5.2 ± 9.50
        HDL-C Week 208 (n=7)
    4.9 ± 4.91
        HDL-C Week 260 (n=5)
    3.4 ± 8.96
        HDL-C EOS (n=7)
    6.7 ± 9.02
        LDL-C Week 12 (n=8)
    -34.1 ± 37.54
        LDL-C Week 24 (n=8)
    -68.5 ± 40.22
        LDL-C Week 52 (n=7)
    -78.5 ± 50.91
        LDL-C Week 104 (n=8)
    -68.7 ± 43.11
        LDL-C Week 156 (n=8)
    -40.8 ± 38.91
        LDL-C Week 208 (n=7)
    -20.5 ± 66.41
        LDL-C Week 260 (n=5)
    -43.4 ± 44.05
        LDL-C EOS (n=7)
    -35.0 ± 42.27
        TG Week 12 (n=8)
    -18.5 ± 71.93
        TG Week 24 (n=8)
    -17.5 ± 37.62
        TG Week 52 (n=7)
    -45.2 ± 66.91
        TG Week 104 (n=8)
    -24.0 ± 84.25
        TG Week 156 (n=8)
    -11.2 ± 60.45
        TG Week 208 (n=7)
    5.6 ± 94.18
        TG Week 260 (n=5)
    -4.8 ± 66.03
        TG EOS (n=7)
    15.7 ± 106.54
    No statistical analyses for this end point

    Secondary: Changes From Baseline In Serum Ferritin

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    End point title
    Changes From Baseline In Serum Ferritin
    End point description
    Changes from Baseline to Week 12, Week 24, Week 52, Week 104, Week 156, Week 208, Week 260, and EOS for serum ferritin. Baseline values were defined as the last measurement prior to the first infusion of sebelipase alfa in Study LAL-CL04. The analysis population includes participants in the FAS for whom serum ferritin data were available at both Baseline and the indicated post-treatment time point. The FAS included all participants who received at least 1 complete infusion of sebelipase alfa in this study and who had at least 1 post-treatment measurement in this study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 52, Week 104, Week 156, Week 208, Week 260, and EOS
    End point values
    Open-Label Sebelipase Alfa
    Number of subjects analysed
    8
    Units: micrograms (µg)/L
    arithmetic mean (standard deviation)
        Week 12 (n=8)
    -37.0 ± 29.93
        Week 24 (n=8)
    -40.1 ± 47.27
        Week 52 (n=7)
    -18.1 ± 32.68
        Week 104 (n=8)
    -22.8 ± 44.57
        Week 156 (n=8)
    0.0 ± 34.50
        Week 208 (n=7)
    18.0 ± 40.41
        Week 260 (n=5)
    63.0 ± 70.53
        EOS (n=7)
    47.7 ± 56.06
    No statistical analyses for this end point

    Secondary: Changes From Baseline In Hs-CRP

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    End point title
    Changes From Baseline In Hs-CRP
    End point description
    Changes from Baseline to Week 12, Week 24, Week 52, Week 104, Week 156, Week 208, Week 260, and EOS for High sensitivity C-reactive protein (hs-CRP). Baseline values were defined as the last measurement prior to the first infusion of sebelipase alfa in Study LAL-CL04. The analysis population includes participants in the FAS for whom hs-CRP data were available at both Baseline and the indicated post-treatment time point. The FAS included all participants who received at least 1 complete infusion of sebelipase alfa in this study and who had at least 1 post-treatment measurement in this study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 52, Week 104, Week 156, Week 208, Week 260, and EOS
    End point values
    Open-Label Sebelipase Alfa
    Number of subjects analysed
    8
    Units: mg/L
    arithmetic mean (standard deviation)
        Week 12 (n=8)
    -1.41 ± 3.022
        Week 24 (n=8)
    -1.03 ± 3.945
        Week 52 (n=7)
    -1.40 ± 3.245
        Week 104 (n=8)
    -1.50 ± 4.079
        Week 156 (n=8)
    -1.09 ± 3.323
        Week 208 (n=7)
    -1.34 ± 3.674
        Week 260 (n=5)
    -0.16 ± 0.619
        EOS (n=7)
    -1.33 ± 2.985
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From after first dose administration post-Baseline through EOS during study LAL-CL04
    Adverse event reporting additional description
    Adverse events were obtained through participant reporting or were elicited by specific questioning or examination of the participant.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Open-Label Sebelipase alfa
    Reporting group description
    -

    Serious adverse events
    Open-Label Sebelipase alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 8 (12.50%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Surgical and medical procedures
    Cholecystectomy
    Additional description: Cholecystectomy for cholelithiasis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Cholecystitis
         subjects affected / exposed
    1 / 8 (12.50%)
         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
    Open-Label Sebelipase alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Hyperaemia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    3
    Hypertension
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    5
    Orthostatic hypotension
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lipoma
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Oral neoplasm benign
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Seasonal allergy
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Chest discomfort
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2
    Chest pain
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    3
    Chills
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2
    Fatigue
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    3
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    4
    Pain
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Cartilage injury
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Iliotibial band syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2
    Laceration
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Procedural dizziness
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Procedural pain
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Sunburn
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    2
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    C-reactive protein increased
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Eosinophil count increased
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Low density lipoprotein increased
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Lymphocyte count increased
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Mean cell volume increased
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Prothrombin time abnormal
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Vitamin B12 decreased
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    White blood cell count increased
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Palpitations
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    2
    Tachycardia
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Choking
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    3
    Dyspnoea
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    5
    Epistaxis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    4
    Laryngeal oedema
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    4
    Rhinorrhoea
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    2
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Clonic convulsion
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Dysarthria
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Dyskinesia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    5
    Headache
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    2
    Lethargy
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2
    Paraesthesia
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    3
    Syncope
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    4
    Tremor
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    4
    Eye disorders
    Blepharitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2
    Conjunctivitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Dry eye
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    3
    Eye pain
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Keratitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Ocular hyperaemia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Vision blurred
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    3
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Abdominal pain
         subjects affected / exposed
    5 / 8 (62.50%)
         occurrences all number
    16
    Abdominal pain upper
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    8
    Diarrhoea
         subjects affected / exposed
    4 / 8 (50.00%)
         occurrences all number
    12
    Dyspepsia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Faeces soft
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Flatulence
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Malocclusion
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    5 / 8 (62.50%)
         occurrences all number
    6
    Toothache
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    2
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Cholelithiasis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Granulomatous liver disease
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Hepatic pain
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Dermal cyst
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2
    Dermatitis acneiform
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Eczema
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Ephelides
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Pigmentation disorder
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Rash macular
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Skin lesion
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Skin mass
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    8
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 8 (50.00%)
         occurrences all number
    7
    Bone pain
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Limb mass
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    3
    Muscle twitching
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    6
    Muscular weakness
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Musculoskeletal pain
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    3
    Myalgia
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    3
    Neck mass
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Spinal pain
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Bacterial vaginosis
    Additional description: Affects only female participants.
         subjects affected / exposed [1]
    1 / 2 (50.00%)
         occurrences all number
    3
    Cellulitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Ear infection
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Ear lobe infection
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Eye infection
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Folliculitis
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    4
    Fungal skin infection
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2
    Infected dermal cyst
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    3
    Influenza
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    3
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    4
    Pharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Rash pustular
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2
    Rhinitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    5
    Subcutaneous abscess
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    5 / 8 (62.50%)
         occurrences all number
    10
    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: This adverse event only affects female participants.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jan 2012
    All changes in site-specific Protocol Amendment #2 were incorporated in this global amendment. This amendment included the following changes among others: • Study duration was updated to define a study period of 3 years. • Duration of investigational medicinal product (IMP) administration was updated to define a period of up to 3 years. • “End of Study” was added to Week 104 in order to define assessments to be completed at the final study visit. • Update with information from preclinical and other clinical studies • Addition / changes to methods + timepoints for analysis • Home infusion details were added for consistency with the synopsis + The criteria for determining a participant’s eligibility for home infusions were further defined • IMP storage instructions were revised • A Per-Protocol Analysis Set was defined • The stopping rules were updated based on preliminary clinical data from LAL-CL01.
    13 Feb 2013
    • Added United States Adopted Name/International non-proprietary drug name. • Exploratory objective was added for evaluation of liver histology to understand long-term effects of sebelipase alfa on liver pathology. • Text clarified to reflect recent clinical experience regarding transient increases in serum lipid levels. • The protocol now allowed planned discontinuation of concomitant lipid-lowering medications (LLM) in participants whose lipid levels have normalised to the point that LLMs may no longer be indicated. • Clarified requirement for discussion with Sponsor and/or documentation around certain concomitant medications and major diet changes. • Stated rationale for obtaining unscheduled electrocardiograms (ECGs) if indicated based on cardiovascular symptoms. • Additional laboratory monitoring schedule of selected analytes in participants undergoing dose modification or change in LLM. • Clarified option for participants to transfer to local site for infusions and study assessments. • Defined inadequate clinical response. • Assessment of other potential causes of suboptimal response prior to dose increase. • Allowed reduction of dose to next lowest level in consultation with the Sponsor and possibly safety committee (SC). • Explained participant discontinuation criteria from the study, including continuation of immunoglobulin E (IgE)-positive participants. • Collection of serum samples for tryptase and antidrug antibodies for participants experiencing Grade 2 or higher suspected immune-mediated IARs. • Requirement for skin testing if IgE negative and IAR suspected to be immune mediated; if skin test positive, continuation only after SC review and agreement of Investigator. • Added optional liver biopsy to be performed anytime between Weeks 52 to 104. • Clarified management and post-IAR activities. • Specific medications were removed from mild IAR to allow for Investigator discretion. • Infusion rate titration recommendations added.
    25 Sep 2014
    • Extended the dosing duration to approximately 5 years, to allow collection of more long term data with sebelipase alfa. Updated the Schedule of Assessments to show that Year 2 assessments applied through Years 3, 4 and 5. • Removed infusion duration time, and revised other text pertaining to preparation and administration of IMP. • Updated information on clinical trial experience with sebelipase alfa, including a cross-reference to the Investigator Brochure where the most updated information resides. • Updated adverse event text and Sponsor information and revised stopping rules to align with other clinical trial protocols for this program.

    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/23348766
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