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    Clinical Trial Results:
    A Multi-center, Open-label, Efficacy and Safety Study of Velaglucerase alfa Enzyme Replacement Therapy in Children and Adolescents with Type 3 Gaucher Disease

    Summary
    EudraCT number
    2012-003427-38
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    15 Mar 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Dec 2018
    First version publication date
    01 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HGT-GCB-068
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01685216
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, United States, MA 02421
    Public contact
    Study Director, Shire, ClinicalTransparency@shire.com
    Scientific contact
    Study Director, Shire, ClinicalTransparency@shire.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000556-PIP01-09
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to explore the efficacy and safety of velaglucerase alfa enzyme replacement therapy (ERT) in children and adolescents with type 3 Gaucher disease.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Sep 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Tunisia: 1
    Country: Number of subjects enrolled
    Egypt: 4
    Country: Number of subjects enrolled
    India: 1
    Worldwide total number of subjects
    6
    EEA total number of subjects
    0
    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)
    5
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 6 centers in Egypt, India, and Tunisia between 14 Sep 2012 (first subject first visit) and 15 Mar 2015 (last subject last visit).

    Pre-assignment
    Screening details
    A total of 7 subjects were enrolled, of them 6 subjects received treatment.

    Pre-assignment period milestones
    Number of subjects started
    6
    Number of subjects completed
    6

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Velaglucerase alfa
    Arm description
    Subjects received an intravenous (IV) infusion of velaglucerase alfa at 60 U/kg, every other week for 1 year, then were followed for 1 month.
    Arm type
    Experimental

    Investigational medicinal product name
    Gene-Activated Human Glucocerebrosidase 400U/vial
    Investigational medicinal product code
    GA-GCB
    Other name
    VELAGLUCERASE ALFA
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an intravenous (IV) infusion of velaglucerase alfa every other week for 1 year.

    Number of subjects in period 1
    Velaglucerase alfa
    Started
    6
    Completed
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Velaglucerase alfa
    Reporting group description
    Subjects received an intravenous (IV) infusion of velaglucerase alfa at 60 U/kg, every other week for 1 year, then were followed for 1 month.

    Reporting group values
    Velaglucerase alfa Total
    Number of subjects
    6
    Age categorical
    Units: Subjects
    Age continuous
    The safety analysis population, included all subjects who received at least 1 study drug infusion (full or partial).
    Units: years
        arithmetic mean (standard deviation)
    5.17 ± 4.446 -
    Gender categorical
    The safety analysis population, included all subjects who received at least 1 study drug infusion (full or partial).
    Units: Subjects
        Female
    1 1
        Male
    5 5

    End points

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    End points reporting groups
    Reporting group title
    Velaglucerase alfa
    Reporting group description
    Subjects received an intravenous (IV) infusion of velaglucerase alfa at 60 U/kg, every other week for 1 year, then were followed for 1 month.

    Primary: Change From Baseline to 12 Months (Week 53) in Hemoglobin Concentration

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    End point title
    Change From Baseline to 12 Months (Week 53) in Hemoglobin Concentration [1]
    End point description
    Hemoglobin concentration was measured as part of the hematology panel or measured separately when the hematology panel was not scheduled. Samples were measured by a central laboratory. Baseline is the modified baseline hemoglobin concentration, the average of the values from screening, baseline, and Week 1/Day 1. A positive change from baseline indicates that hemoglobin concentration increased. The intent-to-treat (ITT) population included all subjects who received at least 1 study drug infusion (full or partial). In the below table, the number of subjects analyzed signifies subjects who were evaluable for this measure
    End point type
    Primary
    End point timeframe
    Baseline, Week 53 or end of study
    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: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    Velaglucerase alfa
    Number of subjects analysed
    5
    Units: Grams per decilitre (g/dL)
    arithmetic mean (standard deviation)
        Hemoglobin
    2.15 ± 1.213
    No statistical analyses for this end point

    Secondary: Change From Baseline to 12 Months (Week 53) in Platelet Count

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    End point title
    Change From Baseline to 12 Months (Week 53) in Platelet Count
    End point description
    Platelet count was measured at a central laboratory as part of the hematology panel. Baseline is the modified baseline platelet count, the average of the values from screening, baseline and Week 1/Day 1. A positive change from baseline indicates that platelet count increased. The ITT population included all subjects who received at least 1 study drug infusion (full or partial). In the below table, the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 53
    End point values
    Velaglucerase alfa
    Number of subjects analysed
    5
    Units: (10^9)/L
    arithmetic mean (standard deviation)
        Platelets
    136.6 ± 51.48
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline to 12 Months (Week 51) in Normalized Liver Volume Measured Using Magnetic Resonance Imaging (MRI)

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    End point title
    Percent Change From Baseline to 12 Months (Week 51) in Normalized Liver Volume Measured Using Magnetic Resonance Imaging (MRI)
    End point description
    Quantitative abdominal MRI was used to measure liver volume. If sedation was necessary to perform an MRI and the investigator deemed that this would be an unwarranted risk to the subject, liver volume could have been measured by ultrasound. Organ volume was measured by a single independent reviewer who was blinded to the subject identification and time point. The liver size relative to body weight was determined using the corresponding body weight measured at the same visit. Change in liver volume is presented as the normalized percentage of body weight. A negative change from baseline indicates that liver volume decreased. The ITT population included all subjects who received at least 1 study drug infusion (full or partial). In the below table, the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 51 or end of study
    End point values
    Velaglucerase alfa
    Number of subjects analysed
    5
    Units: Percent change
    arithmetic mean (standard deviation)
        Normalized Liver Volume
    -30.12 ± 10.366
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline to 12 Months (Week 51) in Normalized Spleen Volume Measured Using Magnetic Resonance Imaging (MRI)

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    End point title
    Percent Change From Baseline to 12 Months (Week 51) in Normalized Spleen Volume Measured Using Magnetic Resonance Imaging (MRI)
    End point description
    Quantitative abdominal MRI was used to measure spleen volume. If sedation was necessary to perform an MRI and the investigator deemed that this would be an unwarranted risk to the subject, spleen volume could have been measured by ultrasound. Organ volume was measured by a single independent reviewer who was blinded to the subject identification and time point. The spleen size relative to body weight was determined using the corresponding body weight measured at the same visit. Change in spleen volume is presented as the normalized percentage of body weight. A negative change from baseline indicates that spleen volume decreased. The ITT population included all subjects who received at least 1 study drug infusion (full or partial). In the below table, the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 51
    End point values
    Velaglucerase alfa
    Number of subjects analysed
    5
    Units: Percent change
    arithmetic mean (standard deviation)
        Normalized Spleen Volume
    -62.27 ± 19.991
    No statistical analyses for this end point

    Secondary: Number of Subjects With Abnormal Neurological Status During the Study

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    End point title
    Number of Subjects With Abnormal Neurological Status During the Study
    End point description
    Neurological symptoms were evaluated at regular intervals during the study and assessed on an individualized basis by a limited, age- and developmental stage-appropriate neurological examination adapted to suit the status of each subject. It was preferred that each neurological examination be performed by a neurologist with experience in assessment of neurological symptoms in patients with Gaucher disease and, if possible, the same neurologist (or designee) who evaluated a given subject at baseline performed the neurological examinations scheduled for that subject during the treatment phase and at the end of study visit. The ITT population included all subjects who received at least 1 study drug infusion (full or partial).
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13, 25, 37, and 53 or end of study
    End point values
    Velaglucerase alfa
    Number of subjects analysed
    6
    Units: Subjects
        Subjects With Abnormal Neurological Status
    6
    No statistical analyses for this end point

    Secondary: Number of Subjects who Experienced a Treatment-Emergent Adverse Event

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    End point title
    Number of Subjects who Experienced a Treatment-Emergent Adverse Event
    End point description
    Adverse events (AEs) were monitored continuously throughout the study from the time the subject or subjects parent/legal guardian signed the informed consent/assent (if applicable) until 30 days after the subject’s last dose of study drug or at the end of study visit and/or until the event resolved or stabilized, or an outcome had been reached, whichever came first. Treatment-emergent adverse events (TEAEs) were defined as AEs which occurred on or after the time of the first infusion until 30 days after the subject’s last study infusion. An infusion-related reaction is defined as an AE that 1) began either during or within 12 hours after the start of the infusion, and 2) was judged as possibly or probably related to study medication. The safety analysis population, included all subjects who received at least 1 study drug infusion (full or partial).
    End point type
    Secondary
    End point timeframe
    From start of study drug administration to follow-up (up to 57 weeks)
    End point values
    Velaglucerase alfa
    Number of subjects analysed
    6
    Units: Subjects
        Any TEAE
    6
        Serious TEAE
    1
        Infusion-related Reaction
    1
    No statistical analyses for this end point

    Secondary: Number of Subject who Developed Anti-Velaglucerase Alfa Antibodies During the Study

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    End point title
    Number of Subject who Developed Anti-Velaglucerase Alfa Antibodies During the Study
    End point description
    Subjects provided blood samples for measurement of anti-velaglucerase alfa antibodies in serum at baseline and approximately every 12 weeks during the treatment phase. Blood samples collected during the treatment phase were to be drawn prior to infusions. Analysis of anti-velaglucerase antibodies used a validated 3-tier immunoassay method (screening, confirmatory, and titer). The ITT population included all subjects who received at least 1 study drug infusion (full or partial).
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13, 25, 37 and 53
    End point values
    Velaglucerase alfa
    Number of subjects analysed
    6
    Units: Subjects
        Baseline
    0
        Week 13
    1
        Week 25
    1
        Week 37
    1
        Week 53
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration to follow-up (up to 57 weeks)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Velaglucerase alfa
    Reporting group description
    Subjects received an intravenous (IV) infusion of velaglucerase alfa at 60 U/kg, every other week for 1 year, then were followed for 1 month.

    Serious adverse events
    Velaglucerase alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Velaglucerase alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    Injury, poisoning and procedural complications
    Excoriation
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Fall
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Chilblains
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Procedural pain
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Cough
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    3
    Rhinorrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Productive cough
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Wheezing
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    2
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Anaemia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    8
    Fine motor delay
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Gross motor delay
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Muscle spasticity
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Strabismus
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Pyrexia
         subjects affected / exposed
    4 / 6 (66.67%)
         occurrences all number
    17
    Influenza like illness
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Asthenia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Gastrointestinal disorders
    Gingival bleeding
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    5
    Inguinal hernia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Heat rash
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Rash papular
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    6
    Bone pain
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    6
    Musculoskeletal pain
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Synovial cyst
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    4
    Acute tonsillitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Hordeolum
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Oral herpes
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Postprocedural cellulitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Dec 2010
    - The patients were to have anemia at screening and at least 1 of 3 additional criteria (at least moderate splenomegaly, thrombocytopenia, or a readily palpable enlarged liver). - Change in the liver and spleen endpoints to indicate that the organ volumes would be determined by magnetic resonance imaging (MRI), not ultrasound, unless sedation would be required to perform the MRI and the investigator deemed that this would pose an unwarranted risk to the patient. - Change in immunoassay methods for evaluation of anti-velaglucerase alfa antibodies: Serum samples will be collected for evaluation of anti-velaglucerase alfa antibodies. Analysis of anti-velaglucerase alfa antibodies will be conducted using validated 3-tier immunoassay methods (screening, confirmatory, and titer) and the anti-velaglucerase alfa antibody positive samples will be further tested for the presence of neutralizing antibodies (NAb).

    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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