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    Clinical Trial Results:
    A Phase 2/3, Multicenter, Randomized, Double-blinded, Placebo-controlled, Repeat-dose Study to Evaluate the Efficacy, Safety, Pharmacodynamics, and Pharmacokinetics of Olipudase Alfa in Patients with Acid Sphingomyelinase Deficiency

    Summary
    EudraCT number
    		 2015-000371-26
    Trial protocol
    		 DE   GB   NL   FR   PT   ES   IT   BE  
    Global end of trial date
    19 Oct 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    31 Oct 2024
    First version publication date
    15 Dec 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    DFI12712
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02004691
    WHO universal trial number (UTN)
    		 U1111-1142-5963
    Sponsors
    Sponsor organisation name
    Sanofi Genzyme
    Sponsor organisation address
    450 Water Street, Cambridge, MA, United States, 02141
    Public contact
    Trial Transparency Team, Sanofi-Aventis Recherche & Développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi-Aventis Recherche & Développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Jan 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this Phase 2/3 study was to evaluate the efficacy of olipudase alfa (recombinant human acid sphingomyelinase) administered intravenously once every 2 weeks for 52 weeks in adult subjects with acid sphingomyelinase deficiency (ASMD) by assessing changes in: 1) spleen volume as measured by abdominal magnetic resonance imaging (MRI); for the United States (US) only, the primary objective was spleen volume in association with subject perception related to spleen volume as measured by splenomegaly-related score (SRS), and 2) infiltrative lung disease as measured by the pulmonary function test diffusing capacity of the lung for carbon monoxide (DLco).
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Dec 2015
    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
    Australia: 2
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Chile: 3
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Türkiye: 2
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Japan: 1
    Country: Number of subjects enrolled
    Brazil: 4
    Worldwide total number of subjects
    36
    EEA total number of subjects
    14
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    35
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 23 active centers in 17 countries. A total of 62 subjects were screened between 18 December 2015 and 22 October 2018, out of which 36 subjects were randomized.

    Pre-assignment
    Screening details
    		 A total of 36 subjects were randomized in a 1:1 ratio to receive either placebo or olipudase alfa in the primary analysis period (PAP) for 52 weeks. After completing PAP, subjects entered an extension treatment period (ETP) where all subjects received olipudase alfa up to Year 5.

    Period 1
    Period 1 title
    PAP: Up to 52 Weeks
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Subjects who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation which was administered IV once every 2 weeks up to Year 5.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo (matched to olipudase alfa) IV infusion once every 2 weeks during the 52 weeks of PAP.

    Arm title
    		 Olipudase alfa
    Arm description
    		 Subjects received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each subject underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Subjects who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olipudase alfa
    Investigational medicinal product code
    GZ402665
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. The dose was escalated to a target dose of 3.0 mg/kg of olipudase alfa.

    Number of subjects in period 1
    		Placebo Olipudase alfa
    Started
    18
    18
    Completed
    17
    18
    Not completed
    1
    0
         Poor compliance
    1
    -
    Period 2
    Period 2 title
    ETP: From Week 52 up to 5 years
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo/Olipudase alfa: PAP/ETP
    Arm description
    		 Subjects received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Subjects who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olipudase alfa
    Investigational medicinal product code
    GZ402665
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. The dose was escalated to a target dose of 3.0 mg/kg of olipudase alfa.

    Arm title
    		 Olipudase alfa/Olipudase alfa: PAP/ETP
    Arm description
    		 Subjects received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each subject underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Subjects who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olipudase alfa
    Investigational medicinal product code
    GZ402665
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. The dose was escalated to a target dose of 3.0 mg/kg of olipudase alfa.

    Number of subjects in period 2
    		Placebo/Olipudase alfa: PAP/ETP Olipudase alfa/Olipudase alfa: PAP/ETP
    Started
    17
    18
    Completed
    13
    16
    Not completed
    4
    2
         Consent withdrawn by subject
    1
    1
         Related to Coronavirus Disease (COVID-19)
    1
    -
         Adverse event not related to COVID-19
    1
    -
         Pregnancy
    1
    -
         Not related to COVID-19
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Subjects who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation which was administered IV once every 2 weeks up to Year 5.

    Reporting group title
    Olipudase alfa
    Reporting group description
    		 Subjects received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each subject underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Subjects who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.

    Reporting group values
    		 Placebo Olipudase alfa Total
    Number of subjects
    		 18 18
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 33.46 ( 17.06 ) 36.17 ( 12.72 ) -
    Gender categorical
    Units: Subjects
        Female
    		 13 9 22
        Male
    		 5 9 14
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 1 1 2
        Black or African American
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        White
    		 16 16 32
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
        Other
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received intravenous (IV) infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Subjects who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation which was administered IV once every 2 weeks up to Year 5.

    Reporting group title
    Olipudase alfa
    Reporting group description
    		 Subjects received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each subject underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Subjects who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.
    Reporting group title
    Placebo/Olipudase alfa: PAP/ETP
    Reporting group description
    		 Subjects received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52. Subjects who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.

    Reporting group title
    Olipudase alfa/Olipudase alfa: PAP/ETP
    Reporting group description
    		 Subjects received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each subject underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP. Subjects who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.

    Primary: Percent Change from Baseline in Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Week 52

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    End point title
    		 Percent Change from Baseline in Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Week 52
    End point description
    Percent predicted Hb and Altitude-adjusted DLco was calculated as: 100*Adjusted DLco/Predicted DLco in unit of mL CO/min/mmHg where, adjusted DLco = Observed DLco (in mL CO/min/mmHg) times Hemoglobin-adjusted factor times Altitude-adjustment factor. Analysis was performed on mITT population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Placebo Olipudase alfa
    Number of subjects analysed
    17
    17
    Units: percent change
        least squares mean (standard error)
    2.961 ( 3.3832 )
    21.968 ( 3.3362 )
    Statistical analysis title
    		 Placebo, Olipudase alfa
    Comparison groups
    Olipudase alfa v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0004 [2]
    Method
    		 Mixed model for repeated measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    19.008
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.319
         upper limit
    		 28.696
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.7576
    Notes
    [1] - The 95% Confidence Interval (CI) and p-values were based on mixed model for repeated measures approach with Baseline Derived % Predicted DLco adjusted for Hb and pressure, age, treatment group, visit, and study visit by treatment group as covariates.
    [2] - Threshold for significance was 0.05.

    Primary: Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Baseline

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    End point title
    		 Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Baseline [3]
    End point description
    Percent predicted Hb and Altitude-adjusted DLco was calculated as: 100*Adjusted DLco/Predicted DLco in unit of mL CO/min/mmHg where, adjusted DLco = Observed DLco (in mL CO/min/mmHg) times Hemoglobin-adjusted factor times Altitude-adjustment factor. Analysis was performed on modified intent-to-treat (mITT) population which included all randomised subjects who had received at least 1 infusion (partial or total) and were analysed according to the treatment arm allocated by randomisation.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1)
    Notes
    [3] - 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: As the primary end point data is descriptive in nature, statistical analysis is not reported.
    End point values
    		 Placebo Olipudase alfa
    Number of subjects analysed
    18
    18
    Units: % Predicted DLco
        arithmetic mean (standard deviation)
    48.45 ( 10.76 )
    49.44 ( 10.99 )
    No statistical analyses for this end point

    Primary: Spleen Volume (in MN) at Baseline

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    End point title
    		 Spleen Volume (in MN) at Baseline [4]
    End point description
    Spleen volume was assessed by abdominal magnetic resonance imaging (MRI) to quantitate the degree of splenomegaly in multiples of normal (MN). Analysis was performed on mITT population.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1)
    Notes
    [4] - 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: As the primary end point data is descriptive in nature, statistical analysis is not reported.
    End point values
    		 Placebo Olipudase alfa
    Number of subjects analysed
    18
    18
    Units: multiples of normal (MN)
        arithmetic mean (standard deviation)
    11.21 ( 3.84 )
    11.69 ( 4.92 )
    No statistical analyses for this end point

    Primary: Percent Change from Baseline in Spleen Volume (in MN) at Week 52

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    End point title
    		 Percent Change from Baseline in Spleen Volume (in MN) at Week 52
    End point description
    Spleen volume was assessed by abdominal MRI to quantitate the degree of splenomegaly in MN. Analysis was performed on mITT population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Placebo Olipudase alfa
    Number of subjects analysed
    17
    18
    Units: percent change
        least squares mean (standard error)
    0.481 ( 2.5002 )
    -39.446 ( 2.4294 )
    Statistical analysis title
    		 Placebo, Olipudase alfa
    Comparison groups
    Placebo v Olipudase alfa
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed model for repeated measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -39.927
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -47.051
         upper limit
    		 -32.803
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4957
    Notes
    [5] - The 95% CI and p-values were based on a mixed model for repeated measures approach with Baseline Spleen Volume (MN), Baseline age, treatment group, study visit, and study visit by treatment group interaction as covariates.
    [6] - Threshold for significance was 0.05.

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) up to Week 52

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) up to Week 52
    End point description
    An AE was defined as any untoward medical occurrence in a subject or clinical investigation subject administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TESAEs was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. Reported AEs are treatment-emergent AEs that developed, worsened or became serious during the treatment period. The safety population was a subset of the randomized population and included randomized subjects who received at least 1 infusion (partial or total).
    End point type
    Secondary
    End point timeframe
    From the first infusion of investigational medicinal product (IMP) up to 52 weeks
    End point values
    		 Placebo Olipudase alfa
    Number of subjects analysed
    18
    18
    Units: subjects
        TEAEs
    18
    18
        TESAEs
    4
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events of Special Interest (AESIs) up to Week 52

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    End point title
    		 Number of Subjects With Adverse Events of Special Interest (AESIs) up to Week 52
    End point description
    An AESI was defined as an AE (serious or nonserious) of scientific and medical concern specific to sponsor's product or program, for which ongoing monitoring and rapid communication by investigator to sponsor was appropriate. AESIs included any pregnancy, symptomatic overdose, dose-limiting toxicities (DLTs) as defined in protocol and infusion associated reactions (IARs). Protocol-defined IARs were AEs that occurred during infusion or within up to 24 hours after the start of infusion and were considered as related or possibly related to the study treatment by the investigator or the sponsor. Events occurring greater than or equal to (>=) 24 hours after the start of an infusion might have been judged an IAR at the discretion of the investigator or sponsor. Algorithm-defined IARs were all AEs that started between the start of infusion and the end of infusion plus 24 hours, irrespective of the perceived relation with study treatment. Analysis was performed on the safety population.
    End point type
    Secondary
    End point timeframe
    From the first infusion of IMP up to 52 weeks
    End point values
    		 Placebo Olipudase alfa
    Number of subjects analysed
    18
    18
    Units: subjects
        Pregnancy
    0
    0
        Symptomatic Overdose
    0
    0
        DLTs
    5
    1
        Protocol-defined IARs
    5
    8
        Algorithm-defined IARs
    13
    15
    No statistical analyses for this end point

    Secondary: Number of Subjects With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52

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    End point title
    		 Number of Subjects With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52
    End point description
    PCSA criteria: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): >3 x upper limit of normal (ULN), >5 x ULN, >10 x ULN and >20 x ULN. Alkaline phosphatase (ALP) >1.5 x ULN. Total bilirubin >1.5 x ULN and >2 x ULN. ALT and total bilirubin: ALT >3 x ULN and total bilirubin >2 x ULN. Baseline was defined as the last non-missing value prior to the first infusion of study treatment. The safety population was a subset of the randomized population and included randomized subjects who received at least 1 infusion (partial or total).
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to 52 weeks
    End point values
    		 Placebo Olipudase alfa
    Number of subjects analysed
    18
    18
    Units: subjects
        ALT: >3 x ULN
    2
    1
        ALT: >5 x ULN
    1
    1
        ALT: >10 x ULN
    0
    0
        ALT: >20 x ULN
    0
    0
        AST: >3 x ULN
    2
    2
        AST: >5 x ULN
    1
    1
        AST: >10 x ULN
    0
    0
        AST: >20 x ULN
    0
    0
        ALP: >1.5 x ULN
    1
    1
        Total Bilirubin: >1.5 x ULN
    4
    4
        Total Bilirubin: >2 x ULN
    1
    4
        ALT >3 x ULN and total bilirubin >2 x ULN
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects who Developed Anti-Drug Antibodies (ADA) to Olipudase Alfa up to Week 52

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    End point title
    		 Number of Subjects who Developed Anti-Drug Antibodies (ADA) to Olipudase Alfa up to Week 52
    End point description
    Number of subjects with treatment-emergent ADA are presented. Baseline was defined as the last non-missing value prior to the first infusion of study treatment. The safety population was a subset of the randomized population and included randomized subjects who received at least 1 infusion (partial or total).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 52
    End point values
    		 Placebo Olipudase alfa
    Number of subjects analysed
    18
    18
    Units: subjects
    1
    4
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Liver Volume (in MN) at Week 52

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    End point title
    		 Percent Change from Baseline in Liver Volume (in MN) at Week 52
    End point description
    Liver volume was assessed by abdominal MRI in MN. Analysis was performed on mITT population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Placebo Olipudase alfa
    Number of subjects analysed
    17
    18
    Units: percent change
        least squares mean (standard error)
    -1.468 ( 2.5409 )
    -28.064 ( 2.4899 )
    Statistical analysis title
    		 Placebo, Olipudase alfa
    Statistical analysis description
    A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in an order the endpoint were reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Placebo v Olipudase alfa
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed model for repeated measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -26.596
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.911
         upper limit
    		 -19.281
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.5862
    Notes
    [7] - The 95% CI and p-values are based on a mixed model for repeated measures approach with Baseline Liver Volume (MN), Baseline age, treatment group, study visit, and study visit by treatment group interaction as covariates.
    [8] - Threshold for significance was 0.05.

    Secondary: Percent Change from Baseline in Platelet Counts at Week 52

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    End point title
    		 Percent Change from Baseline in Platelet Counts at Week 52
    End point description
    Analysis was performed on mITT population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Placebo Olipudase alfa
    Number of subjects analysed
    16
    18
    Units: percent change
        least squares mean (standard error)
    2.490 ( 4.1923 )
    16.822 ( 3.9596 )
    Statistical analysis title
    		 Placebo, Olipudase alfa
    Statistical analysis description
    A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in an order the outcome measure were reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Placebo v Olipudase alfa
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.0185 [10]
    Method
    		 Mixed model for repeated measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    14.332
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.564
         upper limit
    		 26.099
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.7822
    Notes
    [9] - The 95% CI and p-values are based on a mixed model for repeated measures approach with Baseline Platelets, Baseline age, treatment group, study visit, and study visit by treatment group interaction as covariates.
    [10] - Threshold for significance was 0.05.

    Secondary: Change from Baseline in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI)-Item 3 Scale Score at Week 52

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    End point title
    		 Change from Baseline in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI)-Item 3 Scale Score at Week 52
    End point description
    The BFI is a 9-item, validated, self-administered questionnaire that was originally developed to assess fatigue severity. The 9-items were measured on a 0-10 scale, with 0 being ‘does not interfere’ and 10 being ‘completely interferes.’ BFI - Item 3 asks subjects to “Please rate your fatigue (weariness, tiredness) by circling the one number that best describes your worst level of fatigue during the past 24 hours. Numerical rating scale ranges from 0 (no fatigue) to 10 (worst imaginable fatigue). Higher global scores were associated with more severe fatigue. Analysis was performed on mITT population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Placebo Olipudase alfa
    Number of subjects analysed
    17
    17
    Units: score on a scale
        least squares mean (standard error)
    -1.806 ( 0.5272 )
    -1.862 ( 0.5129 )
    Statistical analysis title
    		 Placebo, Olipudase alfa
    Statistical analysis description
    A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in an order the endpoint were reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Placebo v Olipudase alfa
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.94 [12]
    Method
    		 Mixed model for repeated measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.056
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.566
         upper limit
    		 1.454
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.7384
    Notes
    [11] - The 95% CI and p-values are based on a mixed model for repeated measures approach with Baseline BFI item 3 (Worst Fatigue), Baseline age, treatment group, study visit, and study visit by treatment group interaction as covariates.
    [12] - Threshold for significance was 0.05.

    Secondary: Change from Baseline in Dyspnea Severity as Measured by Functional Assessment of Chronic Illness Therapy (FACIT) Dyspnea Scale at Week 52

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    End point title
    		 Change from Baseline in Dyspnea Severity as Measured by Functional Assessment of Chronic Illness Therapy (FACIT) Dyspnea Scale at Week 52
    End point description
    FACIT-Dyspnea: 20 Item assessment split into two 10-item sections.First 10-item section asks subjects about severity of their shortness of breath during various activities. Second 10-item section asks subjects to rate difficulty due to shortness of breath associated with same activities that were referenced in first section. For dyspnea severity items, score range from 0=no shortness of breath; 1=mildly short of breath; 2=moderately short of breath; 3=severely short of breath. For functional limitation items, score range from no difficult=0, A little difficult=1, some difficult=2, and much difficulty=3. Raw score was calculated as: sum of individual item scores*10/number of items answered. Raw scores were then converted to scale scores using table included in FACIT Dyspnea Scale Short Form Scoring Guideline. FACIT dyspnea scale score range: 27.7 to 75.9. Higher score represented high levels of dyspnea. mITT population. Number of subjects analysed=subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Placebo Olipudase alfa
    Number of subjects analysed
    11
    16
    Units: score on a scale
        least squares mean (standard error)
    -6.769 ( 1.9132 )
    -5.862 ( 1.6918 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Pain Severity as Measured by Brief Pain Inventory-Short Form (BPI-SF)-Item 3 Scale Score at Week 52

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    End point title
    		 Change from Baseline in Pain Severity as Measured by Brief Pain Inventory-Short Form (BPI-SF)-Item 3 Scale Score at Week 52
    End point description
    The BPI-SF is a validated, self-administered questionnaire designed to measure a subject’s perceived level of pain. The BPI-SF consisted of 15 items that use a numeric rating scale to assess pain severity and pain interference in the past 24 hours and the past week. For BPI-SF Item 3 asks subjects to “Please rate your pain by marking the box beside the number that best describes your pain at its worst in the past 24 hours.” The numeric rating scale ranged from 0 (no pain) to 10 (worst imaginable pain), where higher scores indicate greater intensity of pain. Analysis was performed on mITT population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Placebo Olipudase alfa
    Number of subjects analysed
    17
    17
    Units: score on a scale
        least squares mean (standard error)
    -2.293 ( 0.5899 )
    -1.404 ( 0.5742 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Splenomegaly-Related Score (SRS) at Week 52 except United States (US), Where it was Part of the Primary 'Combination Spleen Endpoint'

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    End point title
    		 Change From Baseline in Splenomegaly-Related Score (SRS) at Week 52 except United States (US), Where it was Part of the Primary 'Combination Spleen Endpoint'
    End point description
    The SRS rates 5 items: abdominal pain, abdominal discomfort, early satiety, dissatisfaction with abdominal body image, and difficulty to bend down using a numerical rating scale of 0 (absent) to 10 (worst imaginable). The total score of SRS ranges from 0 to 50, with higher scores (50) indicated worst imaginable rating. Analysis was performed on mITT population. Here, number of subjects analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Placebo Olipudase alfa
    Number of subjects analysed
    17
    17
    Units: score on a scale
        least squares mean (standard error)
    -9.281 ( 2.4165 )
    -7.664 ( 2.3481 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For PAP: From the first infusion of IMP up to 52 weeks. For ETP: From Week 52 up to 5 years
    Adverse event reporting additional description
    Analysis performed on safety population. MedDRA version 23.1 used for PAP; MedDRA version 26.0 used for ETP. Any non-serious AE with a preferred term in >=2 % subjects and number of subjects >=2 in the Olipudase Alfa group and the percentage of subjects with the specific TEAE in the Olipudase Alfa group is greater than placebo group.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    PAP: Placebo
    Reporting group description
    		 Subjects received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks up to Week 52.

    Reporting group title
    ETP: Olipudase Alfa/Olipudase Alfa
    Reporting group description
    		 Subjects who completed PAP entered in ETP and continued the same treatment in ETP up to Year 5.

    Reporting group title
    ETP: Placebo/Olipudase Alfa
    Reporting group description
    		 Subjects who completed PAP entered in ETP and crossed over to olipudase alfa with a target maintenance dose of 3 mg/kg after dose escalation which was administered IV once every 2 weeks up to Year 5.

    Reporting group title
    PAP: Olipudase Alfa
    Reporting group description
    		 Subjects received IV infusion of olipudase alfa once every 2 weeks up to Week 52. Each subject underwent a dose escalation according to the following paradigm: 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0,3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 52 weeks of PAP.

    Serious adverse events
    		 PAP: Placebo ETP: Olipudase Alfa/Olipudase Alfa ETP: Placebo/Olipudase Alfa PAP: Olipudase Alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 18 (22.22%)
    5 / 18 (27.78%)
    6 / 17 (35.29%)
    3 / 18 (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)
    Hepatocellular Carcinoma
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (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
    Lower Limb Fracture
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         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
    Vascular disorders
    Shock Haemorrhagic
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis Superficial
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (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
    Aortic Dilatation
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 18 (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
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (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
    Extrasystoles
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (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
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         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
    Loss Of Consciousness
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 17 (11.76%)
    0 / 18 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (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
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (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
    Gastrointestinal disorders
    Inguinal Hernia
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (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
    Hepatobiliary disorders
    Hepatic Haemorrhage
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         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
    Cholecystitis Acute
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 18 (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
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (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
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis Viral
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         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
    Liver Abscess
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (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
    Pneumonia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 18 (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
    Covid-19
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
    0 / 18 (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
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 PAP: Placebo ETP: Olipudase Alfa/Olipudase Alfa ETP: Placebo/Olipudase Alfa PAP: Olipudase Alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 18 (72.22%)
    12 / 18 (66.67%)
    9 / 17 (52.94%)
    17 / 18 (94.44%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 18 (44.44%)
    5 / 18 (27.78%)
    4 / 17 (23.53%)
    12 / 18 (66.67%)
         occurrences all number
    32
    53
    48
    64
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 18 (11.11%)
    3 / 18 (16.67%)
    1 / 17 (5.88%)
    5 / 18 (27.78%)
         occurrences all number
    3
    3
    2
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 18 (5.56%)
    3 / 17 (17.65%)
    4 / 18 (22.22%)
         occurrences all number
    3
    2
    5
    10
    Infections and infestations
    Upper Respiratory Tract Infection
         subjects affected / exposed
    4 / 18 (22.22%)
    3 / 18 (16.67%)
    3 / 17 (17.65%)
    6 / 18 (33.33%)
         occurrences all number
    6
    5
    7
    8
    Covid-19
         subjects affected / exposed
    0 / 18 (0.00%)
    8 / 18 (44.44%)
    7 / 17 (41.18%)
    0 / 18 (0.00%)
         occurrences all number
    0
    9
    8
    0
    Nasopharyngitis
         subjects affected / exposed
    6 / 18 (33.33%)
    7 / 18 (38.89%)
    5 / 17 (29.41%)
    8 / 18 (44.44%)
         occurrences all number
    8
    22
    10
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Sep 2014
    Following changes were made: modification of study title, study organisation, study design, study objectives, changes to assessments.
    05 Dec 2014
    Following changes were made: changed rhASM nomenclature; the primary endpoint was modified to include change from baseline to week 52 in infiltrative lung disease as measured by the diffusing capacity of carbon monoxide (DLco); removed key secondary endpoint and reorganized the secondary endpoints; added a PK sampling timepoint; increased the number of enrolled subjects from approximately 24 to approximately 35; removed requirement to stratify subjects based on baseline spleen volume; subjects assigned to the placebo arm in the PAP were rerandomised 1:1 in the ETP to 1.0 mg/kg or 3.0 mg/kg olipudase alfa; added an interim analysis of the primary endpoint after approximately 20 subjects completed 52 weeks of treatment with study drug.
    28 Jan 2015
    New EudraCT number updated
    08 May 2015
    Following changes were made: added splenomegaly-related symptom efficacy endpoint; changes in the tools used to collect information for the composite secondary efficacy endpoint and included use of an eDiary; clarified that abdominal MRIs and pulmonary imaging by HRCT will be evaluated by readers blinded to subject, treatment arm, and timepoint; demoted to tertiary the secondary efficacy endpoint percentage change in liver function tests ALT and total bilirubin; removed requirement that inpatient hospitalisation was necessary during quarterly visits of years 3 through 5; added a provision for future use of samples; corrected reporting requirements for pregnancy; clarified the “Not applicable” taken regarding action to study drug for an AE; changed the Wilcoxon Mann Whitney test to the ANCOVA method for primary and secondary efficacy endpoint analyses.
    01 Feb 2016
    Following changes were made: removed 1.0 mg arm from the PAP; removed 1.0 mg arm from the ETP; removed “dose comparison”; changed randomisation ratio from 2:1:2 to 1:1 during the PAP; added inclusion criterion for mean splenomegaly-related symptoms score; added contraception requirements following the last olipudase alfa infusion; clarified that the longest study duration per subject will be for at least 3 years and up to 5 years and 3 months dependent upon continued regulatory approval of the protocol; changed interim analysis wording from “interim analysis may be conducted” to “no interim analysis is planned”; clarified subject stopping criteria.
    08 Feb 2017
    Following changes were made: changes in objectives and endpoints; addition of Patient Global Impression of Symptom Severity (PGIS) of ASMD and Patient Global Impression of Change (PGIC); changes in statistical analysis; clarification of time points at which vital signs should be taken; addition of rules on how to resume study drug administration in subjects who have missed infusion; change in some of the dose limiting toxicity (DLT) conditions; change in assessments to be done before rescue treatment was applied; addition of recommendation on usage of cationic amphiphilic antihistamines in rules on concomitant medications; added tobacco use monitoring.
    24 Aug 2017
    Following changes were made: change in 7.2 Exclusion Criteria to include subjects with non-melanoma skin cancer and simplify language; added Lab Values that already were part of Adverse Events of Special Interest (AESIs) to the relevant sections and table; corrected discrepancy of PK Collection; replaced all instances of “after infusion” text with “after the end of infusion” where applicable.
    26 Jan 2018
    Following changes were made: change in subject selection criteria to remove cirrhosis from Exclusion criteria; removed liver biopsy from assessments beyond Week 104; changed the secondary endpoints hierarchical order; clarified language of exclusion criteria.
    18 Sep 2018
    This amendment was made to clarify that portal hypertension would be detected for all subjects using already existing liver ultrasound echo parameters and also to clarify language in statistical analysis and pharmacokinetic assessments.
    05 Dec 2018
    This amendment was made to include the immunogenicity schedule of analysis to be followed in case of drug product from an updated manufacturing process is administered. Also, the language of dose reescalation was clarified.
    12 Aug 2019
    This amendment was made to indicate the different assessments that will be done after manufacturing process update as per regulatory authorities requirements. Previous omissions and errors were corrected. Clarified the plans for interim Clinical Study Report(s).
    15 Apr 2020
    This amendment was made to provide option of home infusion during the COVID-19 pandemic for eligible subjects during the ETP in compliance with applicable country specific regulations and in case of multiple missing infusions, to clarify the process of dose reintroduction, and change the reintroduction starting dose. Previous omissions and errors were corrected. To allow safer reintroduction at a lower level in case of missing >=3 infusions; updated hospitalisation requirements to be more flexible at PI discretion regarding quarterly and yearly visits in ETP.
    02 Feb 2021
    Following changes were made: during a regional or national emergency declared by a governmental agency such as the COVID- 19 pandemic, to allow more flexibility with regard to additional options for monitoring techniques in compliance with applicable country-specific regulations; during a regional or national emergency declared by a governmental agency such as the COVID- 19 pandemic that can lead to site closure or extenuating circumstances that prevent an in-person site visit, for the switch from Process C(48) IMP to the updated manufacturing Process C(32) IMP, adding the possibility to perform the first infusion at home for eligible subjects in agreement between the Sponsor and the Investigator and in compliance with applicable country-specific regulations; liver function test (LFT) monitoring post infusion was already included in this protocol. However, review of the interim data from the clinical development program has identified "Transient elevation in transaminases associated with ceramide release during the dose escalation phase with olipudase alfa" as an important identified risk. Therefore, additional recommendations for the management of transaminase elevation during dose escalation have been added to the protocol; conduct of treatment experience interviews to understand subject’s experience living with acid sphingomyelinase deficiency (ASMD) and participating in this study was added; assessments have been streamlined to reduce subject burden in the extension phase of this trial. Assessments to ensure subject safety have been preserved. This change was implemented after the cutoff date for a planned second database lock of the study for purpose of regulatory submissions in 2021 (the first cutoff on 17 October 2019 was at the end of the PAP); other changes, omissions and corrections were addressed.
    01 Nov 2022
    The reason for this amendment was to allow home infusion to continue until the end of the ETP for subjects who initiated home infusion during the COVID-19 pandemic and continued to be on home infusion at the time of this amendment. This amendment did not apply to Germany. Updated the Sponsor address.

    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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