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    Clinical Trial Results:
    A Multicenter, Open-Label Study of Sebelipase Alfa in Patients with Lysosomal Acid Lipase Deficiency

    Summary
    EudraCT number
    		 2011-004287-30
    Trial protocol
    		 DK   ES   GB   IT   DE   BE   HR   NL  
    Global end of trial date
    28 Dec 2017

    Results information
    Results version number
    		 v3(current)
    This version publication date
    18 Dec 2019
    First version publication date
    21 Jul 2018
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    Based on a response to query from the European Medicines Agency, a discrepancy in the subject disposition regarding the number of participants who withdrew consent during the study was corrected (originally submitted as 2 participants, changed to 1 participant).

    Trial information

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    Trial identification
    Sponsor protocol code
    LAL-CL06
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02112994
    WHO universal trial number (UTN)
    		 U1111-1152-7171
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals Inc.
    Sponsor organisation address
    100 College St., New Haven, United States, 06510
    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
    16 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the safety and efficacy of sebelipase alfa in a broad population of participants with lysosomal acid lipase deficiency.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jun 2014
    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
    Spain: 8
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    United States: 3
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Croatia: 2
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Russian Federation: 1
    Worldwide total number of subjects
    31
    EEA total number of subjects
    18
    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)
    16
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    9
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 21 study centers were initiated in 15 countries, including Australia, Belgium, Brazil, Canada, Croatia, Denmark, Germany, Italy, Mexico, Netherlands, Russia, Spain, Turkey, United Kingdom (UK), and the United States. Seventeen study centers screened at least 1 participant in all of these countries, except the UK and the Netherlands.

    Pre-assignment
    Screening details
    		 The study consisted of a screening period of up to 45 days. The maximum duration of a participant’s participation in the study, inclusive of screening and follow-up visits, was approximately 155 weeks.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    None (Open Label)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 2-<4 Years
    Arm description
    		 This subgroup is part of the full analysis set and includes only participants between the ages of 2 and 4 years old who initiated intravenous (IV) treatment with sebelipase alfa at a dose of 1 milligram/kilogram (mg/kg) every other week (qow). Participants were considered for a dose adjustment at the discretion of the Investigator and in consultation with the Sponsor. Dose escalation to 3 mg/kg qow was considered if pre-defined dose-escalation criteria were met. If these criteria continued to be met, a subsequent dose escalation to 3 mg/kg every week (qw) was considered. Dose decreases as low as 0.35 mg/kg qow were permitted based upon evidence of intolerance to sebelipase alfa treatment. Participants who completed the 96-week treatment period were permitted to continue receiving sebelipase alfa in an expanded treatment period for up to 48 weeks, pending local drug availability and study participation status.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sebelipase Alfa
    Investigational medicinal product code
    Other name
    SBC-102
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All eligible participants received repeat IV infusions of sebelipase alfa at an initial dose of 1 mg/kg qow. Sequential dose escalation to 3 mg/kg qow and 3 mg/kg qw was permitted based on evidence of disease progression. Dose decreases were permitted in the event of poor tolerability or in participants who achieved clinical stability on a dose of 3 mg/kg qw. Consecutive infusions were to be administered at least 7 days apart (for qow dosing) and at least 5 days apart (qw dosing).

    Arm title
    		 4-18 Years
    Arm description
    		 This subgroup is part of the full analysis set and includes only participants between the ages of 4 and 18 years old who initiated IV treatment with sebelipase alfa at a dose of 1 mg/kg qow. Participants were considered for a dose adjustment at the discretion of the Investigator and in consultation with the Sponsor. Dose escalation to 3 mg/kg qow was considered if pre-defined dose-escalation criteria were met. If these criteria continued to be met, a subsequent dose escalation to 3 mg/kg qw was considered. Dose decreases as low as 0.35 mg/kg qow were permitted based upon evidence of intolerance to sebelipase alfa treatment. Participants who completed the 96-week treatment period were permitted to continue receiving sebelipase alfa in an expanded treatment period for up to 48 weeks, pending local drug availability and study participation status.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sebelipase Alfa
    Investigational medicinal product code
    Other name
    SBC-102
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All eligible participants received repeat IV infusions of sebelipase alfa at an initial dose of 1 mg/kg qow. Sequential dose escalation to 3 mg/kg qow and 3 mg/kg qw was permitted based on evidence of disease progression. Dose decreases were permitted in the event of poor tolerability or in participants who achieved clinical stability on a dose of 3 mg/kg qw. Consecutive infusions were to be administered at least 7 days apart (for qow dosing) and at least 5 days apart (qw dosing).

    Arm title
    		 >18 Years
    Arm description
    		 This subgroup is part of the full analysis set and includes only participants greater than 18 years old who initiated IV treatment with sebelipase alfa at a dose of 1 mg/kg qow. Participants were considered for a dose adjustment at the discretion of the Investigator and in consultation with the Sponsor. Dose escalation to 3 mg/kg qow was considered if pre-defined dose-escalation criteria were met. If these criteria continued to be met, a subsequent dose escalation to 3 mg/kg qw was considered. Dose decreases as low as 0.35 mg/kg qow were permitted based upon evidence of intolerance to sebelipase alfa treatment. Participants who completed the 96-week treatment period were permitted to continue receiving sebelipase alfa in an expanded treatment period for up to 48 weeks, pending local drug availability and study participation status.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sebelipase Alfa
    Investigational medicinal product code
    Other name
    SBC-102
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All eligible participants received repeat IV infusions of sebelipase alfa at an initial dose of 1 mg/kg qow. Sequential dose escalation to 3 mg/kg qow and 3 mg/kg qw was permitted based on evidence of disease progression. Dose decreases were permitted in the event of poor tolerability or in participants who achieved clinical stability on a dose of 3 mg/kg qw. Consecutive infusions were to be administered at least 7 days apart (for qow dosing) and at least 5 days apart (qw dosing).

    Number of subjects in period 1
    		2-<4 Years 4-18 Years >18 Years
    Started
    6
    16
    9
    Received at Least 1 Dose of Study Drug
    6
    16
    9
    Received 0.35 mg/kg qow
    0 [1]
    0 [2]
    1 [3]
    Received 1 mg/kg qow
    6
    16
    9
    Received 1 mg/kg qw
    1 [4]
    1 [5]
    0 [6]
    Received 3 mg/kg qow
    3 [7]
    5 [8]
    3 [9]
    Received 3 mg/kg qw
    2 [10]
    1 [11]
    1 [12]
    Completed 96-week Treatment Period
    6
    14
    8
    Completed
    6
    14
    6
    Not completed
    0
    2
    3
         Consent withdrawn by subject
    -
    -
    1
         Liver Transplant
    -
    1
    -
         Progressive Disease
    -
    -
    1
         Pregnancy
    -
    1
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This Milestone represents 1 of the 5 different doses of the study. Dosing was variable and on an individual, per participant basis. All participants began treatment with the study drug at a dose of 1 mg/kg every other week. Dose escalations/reductions could be considered if the participant met protocol-defined criteria. Not all participants in the arm received all 5 different doses.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This Milestone represents 1 of the 5 different doses of the study. Dosing was variable and on an individual, per participant basis. All participants began treatment with the study drug at a dose of 1 mg/kg every other week. Dose escalations/reductions could be considered if the participant met protocol-defined criteria. Not all participants in the arm received all 5 different doses.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This Milestone represents 1 of the 5 different doses of the study. Dosing was variable and on an individual, per participant basis. All participants began treatment with the study drug at a dose of 1 mg/kg every other week. Dose escalations/reductions could be considered if the participant met protocol-defined criteria. Not all participants in the arm received all 5 different doses.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This Milestone represents 1 of the 5 different doses of the study. Dosing was variable and on an individual, per participant basis. All participants began treatment with the study drug at a dose of 1 mg/kg every other week. Dose escalations/reductions could be considered if the participant met protocol-defined criteria. Not all participants in the arm received all 5 different doses.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This Milestone represents 1 of the 5 different doses of the study. Dosing was variable and on an individual, per participant basis. All participants began treatment with the study drug at a dose of 1 mg/kg every other week. Dose escalations/reductions could be considered if the participant met protocol-defined criteria. Not all participants in the arm received all 5 different doses.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This Milestone represents 1 of the 5 different doses of the study. Dosing was variable and on an individual, per participant basis. All participants began treatment with the study drug at a dose of 1 mg/kg every other week. Dose escalations/reductions could be considered if the participant met protocol-defined criteria. Not all participants in the arm received all 5 different doses.
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This Milestone represents 1 of the 5 different doses of the study. Dosing was variable and on an individual, per participant basis. All participants began treatment with the study drug at a dose of 1 mg/kg every other week. Dose escalations/reductions could be considered if the participant met protocol-defined criteria. Not all participants in the arm received all 5 different doses.
    [8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This Milestone represents 1 of the 5 different doses of the study. Dosing was variable and on an individual, per participant basis. All participants began treatment with the study drug at a dose of 1 mg/kg every other week. Dose escalations/reductions could be considered if the participant met protocol-defined criteria. Not all participants in the arm received all 5 different doses.
    [9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This Milestone represents 1 of the 5 different doses of the study. Dosing was variable and on an individual, per participant basis. All participants began treatment with the study drug at a dose of 1 mg/kg every other week. Dose escalations/reductions could be considered if the participant met protocol-defined criteria. Not all participants in the arm received all 5 different doses.
    [10] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This Milestone represents 1 of the 5 different doses of the study. Dosing was variable and on an individual, per participant basis. All participants began treatment with the study drug at a dose of 1 mg/kg every other week. Dose escalations/reductions could be considered if the participant met protocol-defined criteria. Not all participants in the arm received all 5 different doses.
    [11] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This Milestone represents 1 of the 5 different doses of the study. Dosing was variable and on an individual, per participant basis. All participants began treatment with the study drug at a dose of 1 mg/kg every other week. Dose escalations/reductions could be considered if the participant met protocol-defined criteria. Not all participants in the arm received all 5 different doses.
    [12] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This Milestone represents 1 of the 5 different doses of the study. Dosing was variable and on an individual, per participant basis. All participants began treatment with the study drug at a dose of 1 mg/kg every other week. Dose escalations/reductions could be considered if the participant met protocol-defined criteria. Not all participants in the arm received all 5 different doses.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 Pediatric and adult participants initiated IV treatment with sebelipase alfa at a dose of 1 mg/kg qow. Participants were considered for a dose adjustment at the discretion of the Investigator and in consultation with the Sponsor. Dose escalation to 3 mg/kg qow was considered if pre-defined dose-escalation criteria were met. If these criteria continued to be met, a subsequent dose escalation to 3 mg/kg qw was considered. Dose decreases as low as 0.35 mg/kg qow were permitted based upon evidence of intolerance to sebelipase alfa treatment. Participants who completed the 96-week treatment period were permitted to continue receiving sebelipase alfa in an expanded treatment period for up to 48 weeks, pending local drug availability and study participation status.

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 31 31
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 16 16
        Adolescents (12-17 years)
    		 6 6
        Adults (18-64 years)
    		 9 9
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 16.92 ± 14.678 -
    Gender categorical
    Units: Subjects
        Female
    		 12 12
        Male
    		 19 19
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 6 6
        Not Hispanic or Latino
    		 25 25
    Race
    Units: Subjects
        White
    		 27 27
        Other
    		 4 4

    End points

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    End points reporting groups
    Reporting group title
    2-<4 Years
    Reporting group description
    		 This subgroup is part of the full analysis set and includes only participants between the ages of 2 and 4 years old who initiated intravenous (IV) treatment with sebelipase alfa at a dose of 1 milligram/kilogram (mg/kg) every other week (qow). Participants were considered for a dose adjustment at the discretion of the Investigator and in consultation with the Sponsor. Dose escalation to 3 mg/kg qow was considered if pre-defined dose-escalation criteria were met. If these criteria continued to be met, a subsequent dose escalation to 3 mg/kg every week (qw) was considered. Dose decreases as low as 0.35 mg/kg qow were permitted based upon evidence of intolerance to sebelipase alfa treatment. Participants who completed the 96-week treatment period were permitted to continue receiving sebelipase alfa in an expanded treatment period for up to 48 weeks, pending local drug availability and study participation status.

    Reporting group title
    4-18 Years
    Reporting group description
    		 This subgroup is part of the full analysis set and includes only participants between the ages of 4 and 18 years old who initiated IV treatment with sebelipase alfa at a dose of 1 mg/kg qow. Participants were considered for a dose adjustment at the discretion of the Investigator and in consultation with the Sponsor. Dose escalation to 3 mg/kg qow was considered if pre-defined dose-escalation criteria were met. If these criteria continued to be met, a subsequent dose escalation to 3 mg/kg qw was considered. Dose decreases as low as 0.35 mg/kg qow were permitted based upon evidence of intolerance to sebelipase alfa treatment. Participants who completed the 96-week treatment period were permitted to continue receiving sebelipase alfa in an expanded treatment period for up to 48 weeks, pending local drug availability and study participation status.

    Reporting group title
    >18 Years
    Reporting group description
    		 This subgroup is part of the full analysis set and includes only participants greater than 18 years old who initiated IV treatment with sebelipase alfa at a dose of 1 mg/kg qow. Participants were considered for a dose adjustment at the discretion of the Investigator and in consultation with the Sponsor. Dose escalation to 3 mg/kg qow was considered if pre-defined dose-escalation criteria were met. If these criteria continued to be met, a subsequent dose escalation to 3 mg/kg qw was considered. Dose decreases as low as 0.35 mg/kg qow were permitted based upon evidence of intolerance to sebelipase alfa treatment. Participants who completed the 96-week treatment period were permitted to continue receiving sebelipase alfa in an expanded treatment period for up to 48 weeks, pending local drug availability and study participation status.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who received at least 1 infusion of sebelipase alfa. The full analysis set was used for analysis of safety and efficacy.

    Subject analysis set title
    Pediatric Participants
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This sub-group is part of the full analysis set and includes only those participants 18 years old or younger.

    Primary: Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs) [1]
    End point description
    The number of participants experiencing severe TEAEs is presented for each age group who received sebelipase alfa in this open-label study. Information on AEs was obtained at each scheduled contact with the participant (or participant’s parent or legal guardian), by specific questioning and, as appropriate, by examination. An AE was defined as any untoward medical occurrence in a participant that did not necessarily have to have a causal relationship with the administration of the study drug. An AE therefore could have been any unfavorable and unintended sign, symptom or disease temporally associated with the use of the study drug, whether or not considered related to the medicinal product. Pre-existing conditions that worsened in severity during the course of the study were reported as AEs. AEs were recorded from the date of informed consent until completion of the follow-up phone call at 4 weeks after the last infusion of sebelipase alfa administered.
    End point type
    Primary
    End point timeframe
    Week 144
    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: Quantitative statistical analyses were not conducted on any of the reported safety data.
    End point values
    		 2-<4 Years 4-18 Years >18 Years
    Number of subjects analysed
    6
    16
    9
    Units: Participants
    1
    1
    2
    No statistical analyses for this end point

    Secondary: Percent Change In Serum Lipids From Baseline To Week 144

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    End point title
    		 Percent Change In Serum Lipids From Baseline To Week 144
    End point description
    The effect of sebelipase alfa on lipid metabolism was evaluated by measuring the change from baseline to Week 144 in 4 serum lipids: low-density lipoprotein cholesterol (LDL-C); high-density lipoprotein cholesterol (HDL-C); non-HDL-C; triglycerides. Blood samples for these clinical laboratory tests were collected at scheduled time points and analyzed by a central laboratory.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    		 2-<4 Years 4-18 Years >18 Years
    Number of subjects analysed
    5 [2]
    12 [3]
    2 [4]
    Units: Percent Change
    median (full range (min-max))
        LDL-C
    -37.5 (-52 to 25)
    -29.2 (-59 to 23)
    -22.5 (-37 to -8)
        HDL-C
    76.5 (30 to 132)
    24.2 (-4 to 90)
    6.1 (-10 to 22)
        Non-HDL-C
    -39.1 (-53 to 29)
    -26.7 (-62 to 19)
    -22.1 (-33 to -11)
        Triglycerides
    -48.3 (-61 to 11)
    -15.8 (-74 to 112)
    -22.0 (-25 to -19)
    Notes
    [2] - N=5 for all 4 measurements
    [3] - N=12 for all 4 measurements
    [4] - N=2 for all 4 measurements
    No statistical analyses for this end point

    Secondary: Participants Testing Positive For Anti-drug Antibodies (ADAs)

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    End point title
    		 Participants Testing Positive For Anti-drug Antibodies (ADAs)
    End point description
    The impact of ADAs on the safety and immunogenicity of sebelipase alfa was evaluated by testing for ADAs in participants who received sebelipase alfa in this open-label study. Blood samples for assessment were collected prior to study infusions at Week 2, Week 4, Week 8, Week 12, and every 12 weeks thereafter. Participants testing positive for ADAs were also tested for the presence of neutralizing antibodies that inhibited sebelipase alfa enzyme activity and/or cellular uptake. Any participant experiencing a moderate or severe infusion-associated reaction (IAR) was to have an additional assessment of ADAs at the next study visit (prior to study drug infusion); these participants were to also have serum samples collected at 1 to 2 hours after IAR onset and at the next study visit (prior to study drug infusion) for analysis of serum tryptase. The number of participants who became ADA positive and who tested positive for neutralizing antibodies are presented.
    End point type
    Secondary
    End point timeframe
    Week 144
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    31 [5]
    Units: Participants
        ADA Positive
    2
        Neutralizing Antibodies Positive
    0
    Notes
    [5] - Full Analysis Set
    No statistical analyses for this end point

    Secondary: Percent Change In Body Mass Index (BMI)-For-Age Percentile From Baseline To Week 144 in Pediatric Participants

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    End point title
    		 Percent Change In Body Mass Index (BMI)-For-Age Percentile From Baseline To Week 144 in Pediatric Participants
    End point description
    To evaluate the effects of sebelipase alfa on growth parameters in pediatric participants (≤18 years old) presenting with evidence of growth delay, the percent change in the anthropometric parameter of BMI-for-age percentile from Baseline to Week 144 is reported. Anthropometric parameters were plotted on standard growth curves. When possible, historical data on growth parameters was also incorporated into the analyses. Percentiles and Z-scores for BMI-for-age were determined using standard growth charts appropriate to a participant’s age on the date of the assessment: the World Health Organization standard growth chart for participants ≤2 years of age and the Centers for Disease Control standard growth chart for participants >2 years of age.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    		 Pediatric Participants
    Number of subjects analysed
    17 [6]
    Units: Percent Change
        arithmetic mean (standard deviation)
    26.45 ± 118.432
    Notes
    [6] - Pediatric Participants (≤18 years old)
    No statistical analyses for this end point

    Secondary: Shift In Child-Pugh Status From Baseline To Week 144

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    End point title
    		 Shift In Child-Pugh Status From Baseline To Week 144
    End point description
    In order to evaluate the effects of sebelipase alfa on liver function, the number of participants with a shift in Child-Pugh status from Baseline to Week 144 is reported. The status is based on the Child-Pugh score, which is used in clinical practice to assess prognosis in individuals with chronic liver disease. Laboratory data were used in derivation of the score by summing individual scores (scored 1–3, with 3 indicating most severe) from clinical laboratory test results and physical examinations, including total serum bilirubin, serum albumin, prothrombin time, ascites, and hepatic encephalopathy. The total score was used to determine the Child-Pugh status, reported as Class A (score of 5 or 6), Class B (score of 7 to 9), or Class C (score of 10 to 15). Higher scores and higher categories represented a worse outcome. Data reported as 1 of 2 types of shifts in class: No Change from Baseline; Decline from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    Units: Participants
        No Change: A to A
    16
        No Change: B to B
    1
        Decline: A to B
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening (up to 45 days prior to start of treatment) to Week 144.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    0.35 mg/kg QOW
    Reporting group description
    		 This reporting group is based on the safety set and includes AEs with onset during the administration of IV treatment of sebelipase alfa at a dose of 0.35 mg/kg qow.

    Reporting group title
    1.0 mg/kg QOW
    Reporting group description
    		 This reporting group is based on the safety set and includes AEs with onset during the administration of IV treatment of sebelipase alfa at a dose of 1.0 mg/kg qow.

    Reporting group title
    1.0 mg/kg QW
    Reporting group description
    		 This reporting group is based on the safety set and includes AEs with onset during the administration of IV treatment of sebelipase alfa at a dose of 1.0 mg/kg qw.

    Reporting group title
    3.0 mg/kg QOW
    Reporting group description
    		 This reporting group is based on the safety set and includes AEs with onset during the administration of IV treatment of sebelipase alfa at a dose of 3.0 mg/kg qow.

    Reporting group title
    3.0 mg/kg QW
    Reporting group description
    		 This reporting group is based on the safety set and includes AEs with onset during the administration of IV treatment of sebelipase alfa at a dose of 3.0 mg/kg qw.

    Serious adverse events
    		 0.35 mg/kg QOW 1.0 mg/kg QOW 1.0 mg/kg QW 3.0 mg/kg QOW 3.0 mg/kg QW
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    8 / 31 (25.81%)
    0 / 2 (0.00%)
    3 / 11 (27.27%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Shock
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Liver transplant
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 31 (9.68%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 0.35 mg/kg QOW 1.0 mg/kg QOW 1.0 mg/kg QW 3.0 mg/kg QOW 3.0 mg/kg QW
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    30 / 31 (96.77%)
    0 / 2 (0.00%)
    10 / 11 (90.91%)
    4 / 4 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    3
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    2 / 11 (18.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    5
    0
    Hypotension
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Orthostatic hypotension
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 1 (0.00%)
    15 / 31 (48.39%)
    0 / 2 (0.00%)
    4 / 11 (36.36%)
    1 / 4 (25.00%)
         occurrences all number
    0
    26
    0
    4
    1
    Fatigue
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    Vaccination site erythema
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 1 (0.00%)
    7 / 31 (22.58%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
         occurrences all number
    0
    13
    0
    1
    1
    Epistaxis
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 31 (16.13%)
    0 / 2 (0.00%)
    3 / 11 (27.27%)
    1 / 4 (25.00%)
         occurrences all number
    0
    21
    0
    13
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 31 (9.68%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
         occurrences all number
    0
    3
    0
    1
    1
    Catarrh
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    6
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 31 (9.68%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    8
    0
    0
    0
    Bronchospasm
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    6
    0
    1
    0
    Dysphonia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Investigations
    Body temperature increased
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 31 (9.68%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    4
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    0
    1
    1
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    1
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    1
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Protein total decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 31 (12.90%)
    0 / 2 (0.00%)
    3 / 11 (27.27%)
    0 / 4 (0.00%)
         occurrences all number
    0
    6
    0
    6
    0
    Limb injury
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    Bone contusion
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Face injury
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Arthropod bite
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    3
    Concussion
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Forearm fracture
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    2
    Scratch
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Skin abrasion
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Wound
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Cardiac disorders
    Left ventricular dilatation
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 1 (0.00%)
    10 / 31 (32.26%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    27
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 31 (9.68%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Migraine
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    3
    0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Macrocytosis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 1 (0.00%)
    12 / 31 (38.71%)
    0 / 2 (0.00%)
    2 / 11 (18.18%)
    1 / 4 (25.00%)
         occurrences all number
    0
    23
    0
    4
    1
    Abdominal pain
         subjects affected / exposed
    0 / 1 (0.00%)
    11 / 31 (35.48%)
    0 / 2 (0.00%)
    2 / 11 (18.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    17
    0
    2
    0
    Vomiting
         subjects affected / exposed
    0 / 1 (0.00%)
    9 / 31 (29.03%)
    0 / 2 (0.00%)
    2 / 11 (18.18%)
    1 / 4 (25.00%)
         occurrences all number
    0
    20
    0
    2
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 31 (16.13%)
    0 / 2 (0.00%)
    2 / 11 (18.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    7
    0
    3
    0
    Constipation
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 31 (9.68%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    5
    0
    1
    0
    Nausea
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 31 (9.68%)
    0 / 2 (0.00%)
    2 / 11 (18.18%)
    1 / 4 (25.00%)
         occurrences all number
    0
    3
    0
    4
    1
    Dental caries
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    2 / 11 (18.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Oral contusion
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Tongue eruption
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 31 (12.90%)
    0 / 2 (0.00%)
    2 / 11 (18.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    20
    0
    10
    0
    Dermatitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Eczema
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    4
    3
    Erythema
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Petechiae
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
         occurrences all number
    0
    4
    0
    4
    1
    Rash papular
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Skin lesion
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    11
    0
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Endocrine disorders
    Delayed puberty
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 1 (0.00%)
    13 / 31 (41.94%)
    0 / 2 (0.00%)
    4 / 11 (36.36%)
    3 / 4 (75.00%)
         occurrences all number
    0
    29
    0
    6
    4
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 1 (0.00%)
    7 / 31 (22.58%)
    0 / 2 (0.00%)
    2 / 11 (18.18%)
    2 / 4 (50.00%)
         occurrences all number
    0
    8
    0
    2
    3
    Gastroenteritis
         subjects affected / exposed
    0 / 1 (0.00%)
    6 / 31 (19.35%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    2 / 4 (50.00%)
         occurrences all number
    0
    9
    0
    1
    2
    Pharyngitis
         subjects affected / exposed
    0 / 1 (0.00%)
    6 / 31 (19.35%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    8
    0
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 1 (0.00%)
    7 / 31 (22.58%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
         occurrences all number
    0
    14
    0
    1
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    0
    1
    1
    Bronchitis
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 31 (9.68%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 31 (9.68%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Eye infection
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
         occurrences all number
    0
    3
    0
    1
    1
    Influenza
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 31 (9.68%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    5
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    2 / 11 (18.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Otitis media acute
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 31 (9.68%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 31 (9.68%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    5
    0
    6
    0
    Sinusitis
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 31 (9.68%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    Acute sinusitis
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    2
    3
    Hordeolum
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    4
    0
    3
    0
    Tonsillitis
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 31 (3.23%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    3
    0
    0
    1
    Gastritis viral
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Molluscum contagiosum
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Tracheitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 31 (12.90%)
    0 / 2 (0.00%)
    2 / 11 (18.18%)
    0 / 4 (0.00%)
         occurrences all number
    0
    5
    0
    2
    0
    Iron deficiency
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 31 (6.45%)
    0 / 2 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 31 (0.00%)
    0 / 2 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Feb 2015
    − Removed ‘seroconversion rate’ and ‘time to seroconversion’ from the immunogenicity outcome variables. The intent was to characterize ADAs for all isotypes. In this study, a participant was considered to be ADA positive if they had at least 1 positive ADA titer at any time during the study. However, a single positive ADA result would not necessarily imply that a participant had seroconverted. Moreover, analysis of tolerization (for which no standard definition exists) would not be appropriate to these circumstances. − Limited liver biopsy by the transjugular method to participants with advanced liver disease (as local facilities permitted), rather than recommending this for all study participants. − Updated the guidance on the management of IARs based on clinical experience in other ongoing studies with sebelipase alfa. − Clarified that AEs collected during hospitalization would be assessed and reported. − Clarified that AEs occurring after signing the informed consent but before the first dose of study drug would only be recorded if deemed related to study procedures or requirements.
    07 Dec 2015
    - Clarified that the minimum duration of treatment would be “at least 52 weeks.” This clarification was added in response to Pediatric Committee comments on the paediatric investigation plan request for modification. - Added a pharmacokinetics (PK) profile for participants receiving a dose decrease (the protocol already required a PK profile for participants receiving a dose increase), and added an ADA assessment prior to the first infusion at the new dose for all participants receiving a dose modification (increase or decrease). These additional data will support an evaluation of the relationship between immunogenicity, sebelipase alfa exposure, and clinical response during long-term treatment with sebelipase alfa.

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

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