Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

  • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).


    The EU Clinical Trials Register currently displays   43839   clinical trials with a EudraCT protocol, of which   7280   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    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

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

    Close Top of page
    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
    Interim
    Date of interim/final analysis
    15 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Mar 2021
    Global end of trial reached?
    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
    Turkey: 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

    Close Top of page
    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 1 October 2018, out of which 36 subjects were randomised.

    Pre-assignment
    Screening details
    A total of 18 subjects each were randomised to the placebo and the olipudase alfa groups, respectively. Data reported based on date, 15 March 2021. Primary Analysis Period (PAP) is complete.

    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 during the 52 weeks of primary analysis period (PAP). Subjects who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.
    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 during the 52 weeks of PAP. 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.
    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: Ongoing From Week 52
    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 during the 52 weeks of PAP. 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.
    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 during the 52 weeks of PAP. 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.
    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
    0
    0
    Not completed
    17
    18
         Consent withdrawn by subject
    -
    1
         Related to Coronavirus Disease (COVID-19)
    1
    -
         Ongoing
    16
    16
         Unspecified
    -
    1

    Baseline characteristics

    Close Top of page
    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 during the 52 weeks of primary analysis period (PAP). Subjects who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.

    Reporting group title
    Olipudase alfa
    Reporting group description
    Subjects received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.

    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

    Close Top of page
    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 during the 52 weeks of primary analysis period (PAP). Subjects who completed PAP entered in extension treatment period (ETP) and crossed over to olipudase alfa with a target maintenance dose of 3 milligram per kilogram (mg/kg) after dose escalation.

    Reporting group title
    Olipudase alfa
    Reporting group description
    Subjects received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.
    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 during the 52 weeks of PAP. 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.

    Reporting group title
    Olipudase alfa/Olipudase alfa: PAP/ETP
    Reporting group description
    Subjects received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.

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

    Close Top of page
    End point title
    Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Baseline [1]
    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
    [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: As the Baseline endpoint was descriptive in nature, no statistical analysis was performed.
    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: 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

    Close Top of page
    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 [2]
    P-value
    = 0.0004 [3]
    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
    [2] - 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.
    [3] - Threshold for significance was 0.05.

    Primary: Spleen Volume (in MN) at Baseline

    Close Top of page
    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 Baseline endpoint was descriptive in nature, no statistical analysis was performed.
    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

    Close Top of page
    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: Percent Change from Baseline in Liver Volume (in MN) at Week 52

    Close Top of page
    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

    Close Top of page
    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

    Close Top of page
    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 Pain Severity as Measured by Brief Pain Inventory-Short Form (BPI-SF)-Item 3 Scale Score at Week 52

    Close Top of page
    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 Dyspnea Severity as Measured by Functional Assessment of Chronic Illness Therapy (FACIT) Dyspnea Scale at Week 52

    Close Top of page
    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 Splenomegaly-Related Score (SRS) at Week 52

    Close Top of page
    End point title
    Change From Baseline in Splenomegaly-Related Score (SRS) at Week 52
    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

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected from time from first infusion of investigational medicinal product (IMP) to time just prior to first infusion in extension treatment period i.e. up to 52 weeks of PAP regardless of seriousness or relationship to IMP
    Adverse event reporting additional description
    Reported AEs were Treatment Emergent Adverse Events (TEAEs) i.e AEs that developed/worsened during treatment epoch for PAP (time from first infusion of IMP to time just prior to first infusion in ETP if subject had an infusion in ETP or to last date data are available if subject had no infusion in ETP i.e. up to Week 52). Safety population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received IV infusion of placebo (matched to olipudase alfa) once every 2 weeks during the 52 weeks of PAP. 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.

    Reporting group title
    Olipudase alfa
    Reporting group description
    Subjects received IV infusion of olipudase alfa once every 2 weeks during the 52 weeks of PAP. 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.

    Serious adverse events
    Placebo Olipudase alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 18 (22.22%)
    3 / 18 (16.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Lower Limb Fracture
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Shock Haemorrhagic
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic Haemorrhage
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver Abscess
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis Viral
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Placebo Olipudase alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 18 (72.22%)
    17 / 18 (94.44%)
    Nervous system disorders
    Headache
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    8 / 18 (44.44%)
    12 / 18 (66.67%)
         occurrences all number
    32
    64
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 18 (11.11%)
    5 / 18 (27.78%)
         occurrences all number
    3
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    3 / 18 (16.67%)
    4 / 18 (22.22%)
         occurrences all number
    3
    10
    Infections and infestations
    Upper Respiratory Tract Infection
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 18 (22.22%)
    6 / 18 (33.33%)
         occurrences all number
    6
    8
    Nasopharyngitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    6 / 18 (33.33%)
    8 / 18 (44.44%)
         occurrences all number
    8
    18

    More information

    Close Top of page

    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.

    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
    For support, Contact us.
    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.

    European Medicines Agency © 1995-2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA