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    Clinical Trial Results:
    A Multicenter, Randomized, Placebo-controlled Study of SBC-102 in Patients with Lysosomal Acid Lipase Deficiency (ARISE [Acid Lipase Replacement Investigating Safety and Efficacy])

    Summary
    EudraCT number
    		 2011-002750-31
    Trial protocol
    		 DE   GB   IT   ES   CZ   PL   GR   HR   FR  
    Global end of trial date
    12 Dec 2018

    Results information
    Results version number
    		 v3
    This version publication date
    23 Jun 2019
    First version publication date
    06 Aug 2015
    Other versions
    		 v1 (removed from public view) , v2 , v4
    Version creation reason
    • New data added to full data set
    Updated to include data from the Open-label Period of the study.

    Trial information

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    Trial identification
    Sponsor protocol code
    LAL-CL02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01757184
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals Inc.
    Sponsor organisation address
    121 Seaport Blvd, Boston, MA, United States, 02210
    Public contact
    European Clinical Trial Information, Alexion Pharmaceuticals Inc., +33 147100606, clinicaltrials.eu@alexion.com
    Scientific contact
    European Clinical Trial Information, Alexion Pharmaceuticals Inc., +33 147100606, clinicaltrials.eu@alexion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001331-PIP01-12
    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
    12 Dec 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate efficacy of sebelipase alfa relative to placebo, based on normalisation of alanine aminotransferase (ALT) in participants with lysosomal acid lipase deficiency.
    Protection of trial subjects
    Participants have the right to withdraw from the study at any time for any reason without prejudice to further treatment. The investigator and Sponsor also have the right to withdraw participants from the study at any time. Specific reasons for discontinuation may include, but are not restricted to, the following: - intercurrent illness - medical-significant adverse events (AEs), including AEs requiring emergency unblinding - pregnancy - protocol deviation or non-compliance - termination of the study by the sponsor
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Jan 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 30 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Japan: 2
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Russian Federation: 4
    Country: Number of subjects enrolled
    Turkey: 4
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    66
    EEA total number of subjects
    31
    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)
    24
    Adolescents (12-17 years)
    23
    Adults (18-64 years)
    19
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 56 study centers in 17 countries were initiated in this study. Participants were enrolled and treated at 41 centers in 16 countries, including 35 primary centers where participants initiated treatment and 6 qualified local medical centers where participants who were medically stable were transferred for long-term treatment.

    Pre-assignment
    Screening details
    		 To assess eligibility, participants were screened for a period of up to 6 weeks prior to enrollment in the study. A total of 86 participants were screened. Six of these participants underwent re-screening (of which 2 were eligible for the study). In total, 66 participants were eligible for the study and 20 participants were screen failures.

    Period 1
    Period 1 title
    Double-blind Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double-blind Sebelipase Alfa
    Arm description
    		 Double-blind Period: Intravenous (IV) infusions of sebelipase alfa at a dose of 1 milligram/kilogram (mg/kg) administered once every other week (qow).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sebelipase alfa
    Investigational medicinal product code
    SBC-102
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Every other week IV infusions of sebelipase alfa at a dose of 1 mg/kg for 20 weeks.

    Arm title
    		 Double-blind Placebo
    Arm description
    		 Double-blind Period: IV infusions of placebo administered qow.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Every other week IV infusions of matched placebo for 20 weeks.

    Number of subjects in period 1
    		Double-blind Sebelipase Alfa Double-blind Placebo
    Started
    36
    30
    Received at least 1 dose of study drug
    36
    30
    Completed
    35
    30
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -
    Period 2
    Period 2 title
    Open-label Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Open-label Sebelipase Alfa/Sebelipase Alfa
    Arm description
    		 Participants who were randomized to receive sebelipase alfa during the Double-blind Period and also received sebelipase alfa in the Open-label Period. All participants received sebelipase alfa at a dose of 1 mg/kg qow, irrespective of treatment received in the Double-blind Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sebelipase alfa
    Investigational medicinal product code
    SBC-102
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Every other week IV infusions of sebelipase alfa at a dose of 1 mg/kg.

    Arm title
    		 Open-label Placebo/Sebelipase Alfa
    Arm description
    		 Participants who were randomized to receive placebo during the Double-blind Period and received sebelipase alfa in the Open-label Period. All participants received sebelipase alfa at a dose of 1 mg/kg qow, irrespective of treatment received in the Double-blind Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sebelipase alfa
    Investigational medicinal product code
    SBC-102
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Every other week IV infusions of sebelipase alfa at a dose of 1 mg/kg.

    Number of subjects in period 2
    		Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
    Started
    35
    30
    Received at least 1 dose of study drug
    36
    30
    Completed
    34
    29
    Not completed
    2
    1
         Consent withdrawn by subject
    1
    1
         Lost to follow-up
    1
    -
    Joined
    1
    0
         Double-blind participant rechallenged
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double-blind Sebelipase Alfa
    Reporting group description
    		 Double-blind Period: Intravenous (IV) infusions of sebelipase alfa at a dose of 1 milligram/kilogram (mg/kg) administered once every other week (qow).

    Reporting group title
    Double-blind Placebo
    Reporting group description
    		 Double-blind Period: IV infusions of placebo administered qow.

    Reporting group values
    		 Double-blind Sebelipase Alfa Double-blind Placebo Total
    Number of subjects
    		 36 30 66
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 14 10 24
        Adolescents (12-17 years)
    		 9 14 23
        Adults (18-64 years)
    		 13 6 19
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 16.9 ( 11.6 ) 15.2 ( 10.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 18 15 33
        Male
    		 18 15 33
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 6 4 10
        Not Hispanic or Latino
    		 30 26 56
    Race
    Units: Subjects
        Asian
    		 1 0 1
        Japanese
    		 2 0 2
        Black or African American
    		 1 0 1
        White
    		 27 28 55
        Other
    		 5 2 7

    End points

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    End points reporting groups
    Reporting group title
    Double-blind Sebelipase Alfa
    Reporting group description
    		 Double-blind Period: Intravenous (IV) infusions of sebelipase alfa at a dose of 1 milligram/kilogram (mg/kg) administered once every other week (qow).

    Reporting group title
    Double-blind Placebo
    Reporting group description
    		 Double-blind Period: IV infusions of placebo administered qow.
    Reporting group title
    Open-label Sebelipase Alfa/Sebelipase Alfa
    Reporting group description
    		 Participants who were randomized to receive sebelipase alfa during the Double-blind Period and also received sebelipase alfa in the Open-label Period. All participants received sebelipase alfa at a dose of 1 mg/kg qow, irrespective of treatment received in the Double-blind Period.

    Reporting group title
    Open-label Placebo/Sebelipase Alfa
    Reporting group description
    		 Participants who were randomized to receive placebo during the Double-blind Period and received sebelipase alfa in the Open-label Period. All participants received sebelipase alfa at a dose of 1 mg/kg qow, irrespective of treatment received in the Double-blind Period.

    Primary: Percentage Of Participants Achieving Alanine Aminotransferase Normalization

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    End point title
    		 Percentage Of Participants Achieving Alanine Aminotransferase Normalization
    End point description
    Alanine Aminotransferase (ALT) normalization was defined as an abnormal baseline value (ALT > the age- and gender-specific upper limit of normal [ULN] provided by the central laboratory performing the assay) that becomes normal (< ULN). ALT normalization was evaluated at the end of the Double-blind Period (the last Double-blind assessment) and at the end of the Open-label Period (last Open-label assessment). Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last Open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
    End point type
    Primary
    End point timeframe
    Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256)
    End point values
    		 Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
    Number of subjects analysed
    36
    30
    36
    30
    Units: percentage of participants
        number (not applicable)
    31
    7
    56
    37
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    A sample size of 50 randomised participants (approximately 25 participants per treatment group) provided 97% power to detect a statistically significant difference between sebelipase alfa and placebo, using Fisher’s exact test at α=0.05.
    Comparison groups
    Double-blind Sebelipase Alfa v Double-blind Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0271
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Percent Change From Baseline In Low-density Lipoprotein Cholesterol (LDL-C)

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    End point title
    		 Percent Change From Baseline In Low-density Lipoprotein Cholesterol (LDL-C)
    End point description
    Relative reduction (percentage change from baseline) in LDL-C, as assessed by laboratory measurements was evaluated at the end of the Double-blind Period and at the end of the Open-label Period. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last Open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
    End point type
    Secondary
    End point timeframe
    Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
    End point values
    		 Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
    Number of subjects analysed
    36
    30
    36
    30
    Units: percent change
        arithmetic mean (standard deviation)
    -28.42 ( 22.304 )
    -6.25 ( 13.015 )
    -19.74 ( 33.262 )
    -18.09 ( 33.685 )
    Statistical analysis title
    		 Secondary efficacy endpoint
    Comparison groups
    Double-blind Sebelipase Alfa v Double-blind Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Percent Change From Baseline In Non-high Density Lipoprotein Cholesterol (Non-HDL-C)

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    End point title
    		 Percent Change From Baseline In Non-high Density Lipoprotein Cholesterol (Non-HDL-C)
    End point description
    Relative reduction (percent change from baseline) in non-HDL-C, as assessed by laboratory measurements, was evaluated at the end of the Double-blind Period and the Open-label Period. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last Open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
    End point type
    Secondary
    End point timeframe
    Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
    End point values
    		 Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
    Number of subjects analysed
    36
    30
    36
    30
    Units: percent change
        arithmetic mean (standard deviation)
    -27.97 ( 18.612 )
    -6.94 ( 10.922 )
    -19.75 ( 26.875 )
    -18.34 ( 29.177 )
    Statistical analysis title
    		 Secondary efficacy endpoint
    Comparison groups
    Double-blind Sebelipase Alfa v Double-blind Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Percentage Of Participants Achieving Aspartate Aminotransferase Normalization

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    End point title
    		 Percentage Of Participants Achieving Aspartate Aminotransferase Normalization
    End point description
    Aspartate Aminotransferase (AST) normalization was defined as an abnormal baseline value (AST > the age- and gender-specific ULN provided by the central laboratory performing the assay) that becomes normal (< ULN). AST normalization was evaluated at the end of the Double-blind Period (the last Double-blind assessment) and at the end of the Open-label Period (last Open-label assessment). Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last Open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
    End point type
    Secondary
    End point timeframe
    Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
    End point values
    		 Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
    Number of subjects analysed
    36
    29
    36
    29
    Units: Percentage Of Participants
        number (not applicable)
    42
    3
    69
    62
    Statistical analysis title
    		 Secondary efficacy endpoint
    Comparison groups
    Double-blind Sebelipase Alfa v Double-blind Placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Percent Change From Baseline In Triglycerides

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    End point title
    		 Percent Change From Baseline In Triglycerides
    End point description
    Relative reduction (percent change from baseline) in triglycerides, as assessed by laboratory measurements, was evaluated at the end of the Double-blind Period and the Open-label Period. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last Open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
    End point type
    Secondary
    End point timeframe
    Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
    End point values
    		 Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
    Number of subjects analysed
    36
    30
    36
    30
    Units: percent change
        arithmetic mean (standard deviation)
    -25.45 ( 29.411 )
    -11.14 ( 28.827 )
    -11.87 ( 34.580 )
    -19.63 ( 27.066 )
    Statistical analysis title
    		 Secondary efficacy endpoint
    Comparison groups
    Double-blind Sebelipase Alfa v Double-blind Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0375
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Percent Change From Baseline In High-density Lipoprotein Cholesterol (HDL-C)

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    End point title
    		 Percent Change From Baseline In High-density Lipoprotein Cholesterol (HDL-C)
    End point description
    Relative increase (percent change from baseline) in HDL-C, assessed by laboratory measurements, was evaluated at the end of the Double-blind Period and the Open-label Period. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last Open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
    End point type
    Secondary
    End point timeframe
    Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
    End point values
    		 Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
    Number of subjects analysed
    36
    30
    36
    30
    Units: percent change
        arithmetic mean (standard deviation)
    19.57 ( 16.833 )
    -0.29 ( 12.36 )
    31.65 ( 28.971 )
    34.78 ( 29.927 )
    Statistical analysis title
    		 Secondary efficacy endpoint
    Comparison groups
    Double-blind Sebelipase Alfa v Double-blind Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Variability estimate
    Standard deviation

    Secondary: Percent Change From Baseline In Liver Fat Content

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    End point title
    		 Percent Change From Baseline In Liver Fat Content
    End point description
    Decrease in liver fat content, as assessed by magnetic resonance imaging (MRI), was evaluated in participants for whom imaging was performed. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last Open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
    End point type
    Secondary
    End point timeframe
    Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
    End point values
    		 Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
    Number of subjects analysed
    32
    25
    35
    25
    Units: percent change
        arithmetic mean (standard deviation)
    -31.98 ( 26.763 )
    -4.21 ( 15.559 )
    -9.89 ( 32.892 )
    -0.93 ( 37.233 )
    Statistical analysis title
    		 Secondary efficacy endpoint
    Comparison groups
    Double-blind Sebelipase Alfa v Double-blind Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Participants With Improvement In Liver Histopathology (Decrease Of >5% In Hepatic Steatosis Score)

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    End point title
    		 Participants With Improvement In Liver Histopathology (Decrease Of >5% In Hepatic Steatosis Score)
    End point description
    The number of participants who had an improvement in hepatic histopathology (a decrease of >5% in hepatic steatosis score), as determined by blinded central review, in the participants for whom liver biopsy was performed. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group.
    End point type
    Secondary
    End point timeframe
    Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline up to Week 52.
    End point values
    		 Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
    Number of subjects analysed
    16
    10
    12
    6
    Units: participants
    10
    4
    7
    4
    Statistical analysis title
    		 Secondary efficacy endpoint
    Comparison groups
    Double-blind Sebelipase Alfa v Double-blind Placebo
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4216
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Percent Change From Baseline In Liver Volume

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    End point title
    		 Percent Change From Baseline In Liver Volume
    End point description
    Relative reduction (percent change from baseline) in liver volume, as assessed by MRI, was evaluated in participants for whom imaging was performed. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last Open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.
    End point type
    Secondary
    End point timeframe
    Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
    End point values
    		 Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
    Number of subjects analysed
    33
    27
    36
    27
    Units: percent change
        arithmetic mean (standard deviation)
    -10.28 ( 10.51 )
    -2.66 ( 10.107 )
    -24.04 ( 15.792 )
    -21.55 ( 11.727 )
    Statistical analysis title
    		 Secondary efficacy endpoint
    Comparison groups
    Double-blind Sebelipase Alfa v Double-blind Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0068
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Double-blind Period: AEs assessed on or after first infusion of study drug until Week 20. Open-label Period: AEs assessed after first infusion of study drug on Week 22 up to follow-up call (4 weeks [+7 days] after the last infusion).
    Adverse event reporting additional description
    Adverse events were obtained through spontaneous reporting or were elicited by specific questioning of the participant or the participant’s parent or legal guardian.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Double-blind Sebelipase Alfa
    Reporting group description
    		 Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow.

    Reporting group title
    Double-blind Placebo
    Reporting group description
    		 Double-blind Period: IV infusions of placebo administered qow.

    Reporting group title
    Open-label Sebelipase Alfa/Sebelipase Alfa
    Reporting group description
    		 Participants who were randomized to receive sebelipase alfa during the Double-blind Period and also received sebelipase alfa in the Open-label Period. All participants received sebelipase alfa at a dose of 1 mg/kg qow, irrespective of treatment received in the Double-blind Period.

    Reporting group title
    Open-label Placebo/Sebelipase Alfa
    Reporting group description
    		 Participants who were randomized to receive placebo during the Double-blind Period and received sebelipase alfa in the Open-label Period. All participants received sebelipase alfa at a dose of 1 mg/kg qow, irrespective of treatment received in the Double-blind Period.

    Serious adverse events
    		 Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 30 (3.33%)
    6 / 36 (16.67%)
    5 / 30 (16.67%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic cancer
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hyperaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Road traffic accident
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 30 (3.33%)
    0 / 36 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Infusion related reaction
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patellofemoral pain syndrome
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plantar fasciitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Double-blind Sebelipase Alfa Double-blind Placebo Open-label Sebelipase Alfa/Sebelipase Alfa Open-label Placebo/Sebelipase Alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 36 (86.11%)
    28 / 30 (93.33%)
    35 / 36 (97.22%)
    29 / 30 (96.67%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    2
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 36 (19.44%)
    6 / 30 (20.00%)
    15 / 36 (41.67%)
    9 / 30 (30.00%)
         occurrences all number
    7
    6
    20
    18
    Asthenia
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 30 (3.33%)
    1 / 36 (2.78%)
    0 / 30 (0.00%)
         occurrences all number
    3
    1
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 30 (6.67%)
    3 / 36 (8.33%)
    3 / 30 (10.00%)
         occurrences all number
    0
    2
    3
    3
    Vaccination site pain
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 30 (6.67%)
    0 / 36 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    4 / 30 (13.33%)
         occurrences all number
    1
    0
    1
    7
    Malaise
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 30 (3.33%)
    2 / 36 (5.56%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    2
    3
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    4 / 36 (11.11%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    7
    3
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed [1]
    0 / 18 (0.00%)
    1 / 15 (6.67%)
    3 / 18 (16.67%)
    4 / 15 (26.67%)
         occurrences all number
    0
    1
    6
    21
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    6 / 36 (16.67%)
    1 / 30 (3.33%)
    5 / 36 (13.89%)
    6 / 30 (20.00%)
         occurrences all number
    8
    1
    8
    16
    Epistaxis
         subjects affected / exposed
    4 / 36 (11.11%)
    6 / 30 (20.00%)
    5 / 36 (13.89%)
    5 / 30 (16.67%)
         occurrences all number
    8
    7
    24
    9
    Cough
         subjects affected / exposed
    3 / 36 (8.33%)
    3 / 30 (10.00%)
    12 / 36 (33.33%)
    9 / 30 (30.00%)
         occurrences all number
    3
    4
    30
    19
    Rhinorrhoea
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 30 (3.33%)
    8 / 36 (22.22%)
    5 / 30 (16.67%)
         occurrences all number
    2
    1
    25
    9
    Asthma
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    3 / 30 (10.00%)
         occurrences all number
    1
    0
    3
    12
    Rhinitis allergic
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    4 / 36 (11.11%)
    5 / 30 (16.67%)
         occurrences all number
    1
    0
    4
    7
    Nasal congestion
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 30 (3.33%)
    5 / 36 (13.89%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    5
    0
    Productive cough
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    1 / 30 (3.33%)
         occurrences all number
    2
    0
    2
    1
    Autism spectrum disorder
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Sleep disorder
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Investigations
    Body temperature increased
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 30 (3.33%)
    0 / 36 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    4
    1
    0
    2
    Blood cholesterol increased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Eosinophil count increased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Injury, poisoning and procedural complications
    Procedural pain
    Additional description: Procedural pain after liver biopsy unrelated to study drug
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 30 (10.00%)
    0 / 36 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    1
    3
    0
    2
    Ligament sprain
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 30 (3.33%)
    4 / 36 (11.11%)
    3 / 30 (10.00%)
         occurrences all number
    2
    1
    6
    6
    Contusion
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    5 / 36 (13.89%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    5
    2
    Skin abrasion
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    4 / 36 (11.11%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    5
    1
    Arthropod bite
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    3
    2
    Laceration
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 30 (3.33%)
    2 / 36 (5.56%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    3
    2
    Thermal burn
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    2
    2
    Joint injury
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Sunburn
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 30 (6.67%)
    0 / 36 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 36 (27.78%)
    6 / 30 (20.00%)
    19 / 36 (52.78%)
    12 / 30 (40.00%)
         occurrences all number
    17
    7
    56
    33
    Syncope
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    1 / 30 (3.33%)
         occurrences all number
    2
    0
    2
    1
    Dizziness
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 30 (3.33%)
    6 / 36 (16.67%)
    3 / 30 (10.00%)
         occurrences all number
    0
    2
    8
    3
    Somnolence
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 30 (3.33%)
    1 / 36 (2.78%)
    2 / 30 (6.67%)
         occurrences all number
    1
    1
    1
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    2
    1
    Eosinophilia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    1
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    1
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 36 (16.67%)
    5 / 30 (16.67%)
    7 / 36 (19.44%)
    11 / 30 (36.67%)
         occurrences all number
    6
    6
    13
    20
    Abdominal pain
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 30 (3.33%)
    7 / 36 (19.44%)
    9 / 30 (30.00%)
         occurrences all number
    4
    1
    10
    21
    Constipation
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 30 (3.33%)
    4 / 36 (11.11%)
    4 / 30 (13.33%)
         occurrences all number
    3
    1
    4
    5
    Nausea
         subjects affected / exposed
    3 / 36 (8.33%)
    2 / 30 (6.67%)
    5 / 36 (13.89%)
    3 / 30 (10.00%)
         occurrences all number
    3
    2
    7
    4
    Vomiting
         subjects affected / exposed
    3 / 36 (8.33%)
    3 / 30 (10.00%)
    9 / 36 (25.00%)
    7 / 30 (23.33%)
         occurrences all number
    4
    6
    17
    14
    Abdominal pain upper
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 30 (6.67%)
    10 / 36 (27.78%)
    3 / 30 (10.00%)
         occurrences all number
    3
    2
    13
    3
    Odynophagia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 30 (3.33%)
    2 / 36 (5.56%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    6
    8
    Toothache
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    10
    3
    Ascites
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    8
    1
    Abdominal discomfort
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 30 (3.33%)
    1 / 36 (2.78%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    1
    5
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    2 / 30 (6.67%)
         occurrences all number
    1
    0
    1
    2
    Gastritis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Eructation
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Gingival bleeding
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 30 (10.00%)
    2 / 36 (5.56%)
    4 / 30 (13.33%)
         occurrences all number
    3
    4
    3
    4
    Urticaria
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    3 / 36 (8.33%)
    4 / 30 (13.33%)
         occurrences all number
    0
    0
    3
    14
    Dermatitis allergic
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    6 / 30 (20.00%)
         occurrences all number
    0
    0
    0
    12
    Ecchymosis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    2 / 30 (6.67%)
         occurrences all number
    1
    0
    1
    9
    Dermatitis atopic
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    4
    3
    Eczema
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    1
    3
    Pruritus
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    1
    0
    0
    3
    Dermatitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 30 (3.33%)
    3 / 36 (8.33%)
    4 / 30 (13.33%)
         occurrences all number
    2
    1
    3
    9
    Musculoskeletal pain
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    3 / 36 (8.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    0
    3
    3
    Back pain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    5
    1
    Osteoporosis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Neck pain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Tendonitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    2
    2
    Pain in extremity
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    3 / 36 (8.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Myalgia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 30 (3.33%)
    0 / 36 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    1
    0
    3
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 36 (16.67%)
    6 / 30 (20.00%)
    10 / 36 (27.78%)
    5 / 30 (16.67%)
         occurrences all number
    8
    7
    25
    9
    Nasopharyngitis
         subjects affected / exposed
    4 / 36 (11.11%)
    3 / 30 (10.00%)
    17 / 36 (47.22%)
    14 / 30 (46.67%)
         occurrences all number
    4
    3
    61
    28
    Sinusitis
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 30 (0.00%)
    4 / 36 (11.11%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    4
    0
    Rhinitis
         subjects affected / exposed
    2 / 36 (5.56%)
    3 / 30 (10.00%)
    4 / 36 (11.11%)
    9 / 30 (30.00%)
         occurrences all number
    2
    3
    7
    17
    Tonsillitis
         subjects affected / exposed
    2 / 36 (5.56%)
    4 / 30 (13.33%)
    4 / 36 (11.11%)
    3 / 30 (10.00%)
         occurrences all number
    2
    4
    5
    3
    Pharyngitis
         subjects affected / exposed
    0 / 36 (0.00%)
    5 / 30 (16.67%)
    6 / 36 (16.67%)
    5 / 30 (16.67%)
         occurrences all number
    0
    5
    7
    8
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 30 (6.67%)
    0 / 36 (0.00%)
    4 / 30 (13.33%)
         occurrences all number
    0
    2
    0
    16
    Varicella
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 30 (10.00%)
    1 / 36 (2.78%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    3 / 36 (8.33%)
    5 / 30 (16.67%)
         occurrences all number
    0
    0
    8
    20
    Gastroenteritis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    5 / 36 (13.89%)
    7 / 30 (23.33%)
         occurrences all number
    0
    0
    5
    11
    Bronchitis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 30 (3.33%)
    2 / 36 (5.56%)
    3 / 30 (10.00%)
         occurrences all number
    0
    1
    3
    3
    Influenza
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 30 (3.33%)
    3 / 36 (8.33%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    3
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    2
    3
    Conjunctivitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    3 / 30 (10.00%)
         occurrences all number
    0
    0
    1
    3
    Oral herpes
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    1 / 36 (2.78%)
    3 / 30 (10.00%)
         occurrences all number
    1
    0
    1
    3
    Vulvovaginitis
         subjects affected / exposed [2]
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    2
    Otitis media
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    3 / 36 (8.33%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Viral infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 30 (3.33%)
    0 / 36 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    1
    0
    3
    Gastroenteritis viral
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    3
    Gastrointestinal infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    1
    0
    0
    3
    Ear infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    2 / 36 (5.56%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Rotavirus infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    0 / 36 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    8 / 36 (22.22%)
    4 / 30 (13.33%)
         occurrences all number
    0
    0
    11
    4
    Iron deficiency
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 30 (0.00%)
    3 / 36 (8.33%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    3
    2
    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: Adverse event occurring in female participants only.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Adverse event occurring in female participants only.

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2015
    • Modified the antidrug antibodies (ADA) safety endpoint to remove characterization of seroconversion and tolerization. • Clarified that lysosomal acid lipase enzyme activity and deoxyribonucleic acid (DNA) blood sampling would not be repeated if a participant underwent rescreening. • Added assessments of selected laboratory parameters before and/or after any dose change or change in lipid-lowering medication (LLM). • Clarified that the blood sample for the liver panel should be obtained before the liver biopsy due to the potential of a transient elevation of hepatic transaminases after a liver biopsy. • Allowed the dose (mg) of sebelipase alfa to be determined based on a participant’s last available weight measurement if weight could not be obtained on the day of the infusion due to the participant’s condition. • Replaced “inadequate clinical response” with “criteria for dose escalation,” as dose escalation may also be required for persistent disease progression. • Replaced “infusion related reaction” with “infusion-associated reaction. • Updated the guidance on management of infusion-associated reactions. • Updated and clarified safety reporting timelines.
    16 Mar 2015
    •Modified the safety endpoint for immunogenicity to remove reference to seroconversion and tolerization. • Added clarifications: Screening assessments of LAL enzyme activity and DNA sampling did not need to be repeated if a participant rescreened for the study; the blood sample for the liver panel should be obtained before the liver biopsy due to the potential of a transient elevation of hepatic transaminases after a liver biopsy. • In the dose escalation criteria, added criteria for “significant clinical progression of liver disease.” Also removed the term “inadequate clinical response” when describing dose escalation criteria, as dose escalation may be required for persistent disease progression as well as inadequate clinical response. • Added collection of blood sample for selected laboratory tests in participants who had a dose modification or a change in LLM. • Added the following for the first 12 weeks after a dose increase: Vital sign monitoring was extended to 2 hours postinfusion (if the participant had been previously approved for a decrease in postinfusion vital sign monitoring); recommended that the infusion should be administered over 2 hours; participants previously on home infusion were required to return to study site for infusions and follow dose escalation recommendations for laboratory assessments and vital sign collection. • Corrected the study duration from 150 to 152 weeks (to account for the 2 weeks between the end of the Double-blind Period at Week 20 and the beginning of the Open-label Extension Period at Week 22). • In Schedule of Assessments, indicated that the screening period extended to Day 0, and that carbohydrate deficient transferrin should be assessed preinfusion at Week 0. • Allowed the dose (mg) of sebelipase alfa to be determined based on a participant’s last available weight measurement if weight could not be obtained on the day of the infusion due to the participant's condition. • Updated safety reporting information.
    20 Nov 2015
    • Added a 104 week Open-label Expanded Treatment Period, to ensure that all participants continue to have access to treatment until sebelipase alfa is registered and available in their study region. • Added an additional liver biopsy during long-term treatment in the Open-label Extension Period. This biopsy could be obtained on an optional basis between Week 104 and Week 152. • Added serial pharmacokinetics assessments and a predose ADA assessment for participants who received a dose modification, to be performed at the time of the first infusion at the new dose/schedule.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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