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    Clinical Trial Results:
    A Randomized, Placebo-Controlled, Blind-Start, Single-Crossover Phase 3 Study to Assess the Efficacy and Safety of UX003 rhGUS Enzyme Replacement Therapy in Patients with MPS VII

    Summary
    EudraCT number
    2014-005638-71
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    04 May 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    31 Mar 2019
    First version publication date
    23 Jul 2017
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Updates to subject disposition, baseline characteristics and endpoint descriptions

    Trial information

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    Trial identification
    Sponsor protocol code
    UX003-CL301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02230566
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Ultragenyx Pharmaceutical Inc
    Sponsor organisation address
    60 Leveroni Court, Novato, United States, 94949
    Public contact
    Robert Hostutler, Sr. Clinical Program Manager, Clinical Operations, 1 4154838148, rhostutler@ultragenyx.com
    Scientific contact
    Christine Haller, MD, VP, Drug Safety and Pharmacovigilance, 1 4154838937, challer@ultragenyx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001540-PIP01-13
    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
    04 May 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In the European Union (EU) and rest of world, efficacy of UX003 in mucopolysaccharidosis VII MPS VII subjects is determined by the percent reduction of urinary glycosaminoglycan (uGAG) excretion after 24 weeks of treatment relative to the pre-treatment baseline. In the United States (US) only, efficacy of UX003 in MPS VII subjects is based on the totality of the clinical data on a per subject basis.
    Protection of trial subjects
    The trial was designed, conducted, recorded, and reported in accordance with the principles established by the 18th World Medical Association General Assembly (Helsinki, 1964) and subsequent amendments and clarifications adopted by the General Assemblies. The investigators made every effort to ensure that the study was conducted in full conformance with Helsinki principles, International Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines, current Food and Drug Administration (FDA) regulations, EU Clinical Trial Directive 2001/20/EC, and local ethical and regulatory requirements. Each investigator was thoroughly familiar with the appropriate administration and potential risks of administration of the study drug, as described in the protocol and Investigator’s Brochure, prior to the initiation of the study. The method of obtaining and documenting informed consent and the contents of the informed consent form (ICF) complied with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of Human Subjects,” the Health Insurance Portability and Accountability Act regulations, and all other applicable regulatory requirements. Investigators were responsible for preparing the ICF and submitting it to the Sponsor for approval prior to submission to the Institutional Review Board (IRB). All ICFs were written in regional language and contained the minimum elements for consent as mandated by the ICH guidelines. An IRB-approved ICF was provided by the Sponsor prior to initiation of the study. Investigators obtained signed written informed consent from each potential study subject prior to the conduct of any study procedures and after the methods, objectives, requirements, and potential risks of the study were fully explained to each potential subject. Consent for participation could be withdrawn at any time for any reason by the subject.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Dec 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research
    Long term follow-up duration
    36 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 12
    Worldwide total number of subjects
    12
    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)
    4
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    3
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects were evaluated for trial participation based on the protocol-specified inclusion and exclusion criteria. There were 14 subjects screened, of which 12 enrolled and completed the study. Two subjects withdrew consent prior to enrollment.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    The study was conducted as a randomized, double-blind, blind start, single crossover, placebo-controlled study. Double-blind conditions were established so that neither the sponsor, subject, or site personnel involved in study conduct knew the identity of a subject’s treatment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group A: 4 mg/kg UX003
    Arm description
    4 mg/kg UX003 every other week (QOW) through Week 46
    Arm type
    Experimental

    Investigational medicinal product name
    UX003
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    UX003 is a sterile liquid buffered saline formulation of recombinant human betaglucuronidase (rhGUS) at a concentration of 2 mg/mL filled to allow the withdrawal of a 5.0 mL deliverable volume and supplied in a 10 mL glass vial. Dosage of UX003 is 4 mg/kg body weight administered QOW by slow intravenous (IV) infusion over a period of approximately 4 hours.

    Arm title
    Group B: 8 Weeks Placebo Then 4 mg/kg UX003
    Arm description
    Placebo QOW for the first 8 weeks followed by 4 mg/kg UX003 QOW through Week 46
    Arm type
    Experimental

    Investigational medicinal product name
    UX003
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    UX003 is a sterile liquid buffered saline formulation of recombinant human betaglucuronidase (rhGUS) at a concentration of 2 mg/mL filled to allow the withdrawal of a 5.0 mL deliverable volume and supplied in a 10 mL glass vial. Dosage of UX003 is 4 mg/kg body weight administered QOW by slow intravenous (IV) infusion over a period of approximately 4 hours.

    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
    A placebo consisting of the UX003 formulation buffer (without rhGUS) will be administered IV QOW to Groups B-D over a period of approximately 4 hours during the respective placebo treatment portion of the Blinded Period.

    Arm title
    Group C: 16 Weeks Placebo Then 4 mg/kg UX003
    Arm description
    Placebo QOW for the first 16 weeks followed by 4 mg/kg UX003 QOW through Week 46
    Arm type
    Experimental

    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
    A placebo consisting of the UX003 formulation buffer (without rhGUS) will be administered IV QOW to Groups B-D over a period of approximately 4 hours during the respective placebo treatment portion of the Blinded Period.

    Investigational medicinal product name
    UX003
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    UX003 is a sterile liquid buffered saline formulation of recombinant human betaglucuronidase (rhGUS) at a concentration of 2 mg/mL filled to allow the withdrawal of a 5.0 mL deliverable volume and supplied in a 10 mL glass vial. Dosage of UX003 is 4 mg/kg body weight administered QOW by slow intravenous (IV) infusion over a period of approximately 4 hours.

    Arm title
    Group D: 24 Weeks Placebo Then 4 mg/kg UX003
    Arm description
    Placebo QOW for the first 24 weeks followed by 4 mg/kg UX003 QOW through Week 46
    Arm type
    Experimental

    Investigational medicinal product name
    UX003
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    UX003 is a sterile liquid buffered saline formulation of recombinant human betaglucuronidase (rhGUS) at a concentration of 2 mg/mL filled to allow the withdrawal of a 5.0 mL deliverable volume and supplied in a 10 mL glass vial. Dosage of UX003 is 4 mg/kg body weight administered QOW by slow intravenous (IV) infusion over a period of approximately 4 hours.

    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
    A placebo consisting of the UX003 formulation buffer (without rhGUS) will be administered IV QOW to Groups B-D over a period of approximately 4 hours during the respective placebo treatment portion of the Blinded Period.

    Number of subjects in period 1
    Group A: 4 mg/kg UX003 Group B: 8 Weeks Placebo Then 4 mg/kg UX003 Group C: 16 Weeks Placebo Then 4 mg/kg UX003 Group D: 24 Weeks Placebo Then 4 mg/kg UX003
    Started
    3
    3
    3
    3
    Completed
    3
    3
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A: 4 mg/kg UX003
    Reporting group description
    4 mg/kg UX003 every other week (QOW) through Week 46

    Reporting group title
    Group B: 8 Weeks Placebo Then 4 mg/kg UX003
    Reporting group description
    Placebo QOW for the first 8 weeks followed by 4 mg/kg UX003 QOW through Week 46

    Reporting group title
    Group C: 16 Weeks Placebo Then 4 mg/kg UX003
    Reporting group description
    Placebo QOW for the first 16 weeks followed by 4 mg/kg UX003 QOW through Week 46

    Reporting group title
    Group D: 24 Weeks Placebo Then 4 mg/kg UX003
    Reporting group description
    Placebo QOW for the first 24 weeks followed by 4 mg/kg UX003 QOW through Week 46

    Reporting group values
    Group A: 4 mg/kg UX003 Group B: 8 Weeks Placebo Then 4 mg/kg UX003 Group C: 16 Weeks Placebo Then 4 mg/kg UX003 Group D: 24 Weeks Placebo Then 4 mg/kg UX003 Total
    Number of subjects
    3 3 3 3 12
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    13.13 ± 1.656 12.50 ± 4.004 20.77 ± 3.004 15.23 ± 8.633 -
    Gender categorical
    Units: Subjects
        Female
    3 2 3 0 8
        Male
    0 1 0 3 4

    End points

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    End points reporting groups
    Reporting group title
    Group A: 4 mg/kg UX003
    Reporting group description
    4 mg/kg UX003 every other week (QOW) through Week 46

    Reporting group title
    Group B: 8 Weeks Placebo Then 4 mg/kg UX003
    Reporting group description
    Placebo QOW for the first 8 weeks followed by 4 mg/kg UX003 QOW through Week 46

    Reporting group title
    Group C: 16 Weeks Placebo Then 4 mg/kg UX003
    Reporting group description
    Placebo QOW for the first 16 weeks followed by 4 mg/kg UX003 QOW through Week 46

    Reporting group title
    Group D: 24 Weeks Placebo Then 4 mg/kg UX003
    Reporting group description
    Placebo QOW for the first 24 weeks followed by 4 mg/kg UX003 QOW through Week 46

    Subject analysis set title
    Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study, based on the blind-start design.

    Subject analysis set title
    UX003 Active Treatment
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received 4 mg/kg UX003 QOW per group assignment (based on the blind-start design) and were dosed through Week 46. All groups received a minimum of 24 weeks of treatment with UX003.

    Subject analysis set title
    UX003 4 mg/kg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Subjects were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.

    Primary: European Union (EU) and Rest of World: Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate (DS) at UX003 Treatment Week 24

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    End point title
    European Union (EU) and Rest of World: Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate (DS) at UX003 Treatment Week 24 [1]
    End point description
    Baseline was defined as the average of all assessments prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect was subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Percent change from baseline in uGAG DS was analyzed by generalized estimating equation (GEE) modeling based on observed data. The GEE model included included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable. In the United States (US), this was considered a secondary outcome measure. Per guidance from the Food and Drug Administration (FDA), no primary efficacy variable was declared in the US. Efficacy was to be based on the totality of the clinical data on a per subject basis.
    End point type
    Primary
    End point timeframe
    Baseline (defined as the average of all assessments prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
    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: Statistical analysis data are included in the attachments section (see zip file).
    End point values
    UX003 4 mg/kg
    Number of subjects analysed
    12 [2]
    Units: percentage change
        least squares mean (standard error)
    -64.82 ± 2.468
    Attachments
    Untitled (Filename: uGAG excretion statistical analysis.docx)
    Notes
    [2] - subjects who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment
    No statistical analyses for this end point

    Secondary: Multi-Domain Responder Index (MDRI) Score at UX003 Treatment Week 24

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    End point title
    Multi-Domain Responder Index (MDRI) Score at UX003 Treatment Week 24
    End point description
    MDRI score, calculated as the total response score at UX003 Treatment Week 24 across 6 domains: 6-Minute Walk Test, forced vital capacity predicted value, shoulder flexion, visual acuity, and Bruininks-Oseretsky Test of Motor Proficiency fine motor and gross motor capacity. For each domain, a minimally important difference (MID) was prespecified. Changes from before treatment (baseline) to 24 weeks after treatment in each domain variable were scored against pre-specified MIDs. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) An improvement or decline ≥ MID was scored either as a +1 or -1, respectively, and a change <MID was scored as 0. The integration of benefit occurred by summing the responses (-1, +1, 0) across all 6 domain variables to derive the MDRI score, with a range of -6 (greatest possible decline) to +6 (greatest possible improvement).
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
    End point values
    UX003 4 mg/kg
    Number of subjects analysed
    12
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.5 ± 0.8
    Attachments
    Untitled (Filename: MDRI statistical analysis.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in 6MWT at UX003 Treatment Week 24

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    End point title
    Change From Baseline in 6MWT at UX003 Treatment Week 24
    End point description
    The total distance walked (in meters) in a 6-minute period was measured. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) A positive change from Baseline indicates improvement. Change from baseline in 6MWT was analyzed by GEE modeling based on observed data. The GEE model included all subjects who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable.
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
    End point values
    UX003 4 mg/kg
    Number of subjects analysed
    9 [3]
    Units: meters
        least squares mean (standard error)
    20.8 ± 16.75
    Attachments
    Untitled (Filename: 6MWT statistical analysis.docx)
    Notes
    [3] - subjects who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pulmonary Function Testing: FVC%pred at UX003 Treatment Week 24

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    End point title
    Change From Baseline in Pulmonary Function Testing: FVC%pred at UX003 Treatment Week 24
    End point description
    Spirometry was administered to subjects who did not require invasive ventilatory support or have a tracheostomy and measured percentage of predicted FVC. The percent predicted values were calculated after testing using published normative data. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) No GEE analysis was performed for FVC due to the limitation of the sample size.
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
    End point values
    UX003 4 mg/kg
    Number of subjects analysed
    1 [4]
    Units: percentage predicted FVC
        arithmetic mean (standard deviation)
    0 ± 99999
    Notes
    [4] - 99999=not applicable (1 subject had non-missing change from baseline at UX003 Treatment Week 24).
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pulmonary Function Testing: Maximum Ventilatory Ventilation (MVV) at UX003 Treatment Week 24

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    End point title
    Change From Baseline in Pulmonary Function Testing: Maximum Ventilatory Ventilation (MVV) at UX003 Treatment Week 24
    End point description
    Spirometry was administered to subjects who did not require invasive ventilatory support or have a tracheostomy to measure MVV. The percent predicted values were calculated after testing using published normative data. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.)
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
    End point values
    UX003 4 mg/kg
    Number of subjects analysed
    0 [5]
    Units: L/m
        arithmetic mean (standard deviation)
    ±
    Notes
    [5] - no change from baseline calculated due to lack of data at baseline and/or UX003 Treatment Week 24
    No statistical analyses for this end point

    Secondary: Change From Baseline in Shoulder Flexion and Extension Maximum Range of Motion at UX003 Treatment Week 24

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    End point title
    Change From Baseline in Shoulder Flexion and Extension Maximum Range of Motion at UX003 Treatment Week 24
    End point description
    Goniometry was used to measure (in degrees) the maximum passive shoulder range of motion in both flexion and extension. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in shoulder flexion left was analyzed by GEE modeling based on observed data. The GEE model included all subjects who had nonmissing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable.
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
    End point values
    UX003 4 mg/kg
    Number of subjects analysed
    12 [6]
    Units: degrees
    least squares mean (standard error)
        Shoulder flexion - left; n=12
    -6.5 ± 4.86
        Shoulder extension - left; n=11
    -1.5 ± 4.83
        Shoulder flexion - right; n=12
    -1.8 ± 3.54
        Shoulder extension - right; n=11
    -3.4 ± 3.48
        Tighter shoulder flexion; n=12
    -9.4 ± 4.6
        Tighter shoulder extension; n=11
    -6.7 ± 3.53
    Attachments
    Untitled (Filename: shoulder flexion_extension statistical analyses.docx)
    Notes
    [6] - subjects who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment
    No statistical analyses for this end point

    Secondary: Change From Baseline in Uncorrected Visual Acuity at UX003 Treatment Week 24

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    End point title
    Change From Baseline in Uncorrected Visual Acuity at UX003 Treatment Week 24
    End point description
    Visual acuity was measured (corrected and uncorrected) using a standard eye chart and recorded for each eye independently. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. The change in the number of lines from pre-treatment baseline to 24 weeks of treatment was evaluated. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) A positive change from baseline indicates improvement. Change from baseline in uncorrected visual acuity was analyzed by GEE modeling based on observed data. The GEE model included all subjects who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable.
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
    End point values
    UX003 4 mg/kg
    Number of subjects analysed
    7 [7]
    Units: lines
    least squares mean (standard error)
        Left eye
    1 ± 0.63
        Right eye
    0.9 ± 0.51
    Attachments
    Untitled (Filename: visual acuity statistical analyses.docx)
    Notes
    [7] - subjects who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment
    No statistical analyses for this end point

    Secondary: Change From Baseline in BOT-2 Scores at UX003 Treatment Week 24

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    End point title
    Change From Baseline in BOT-2 Scores at UX003 Treatment Week 24
    End point description
    BOT-2 was administered to evaluate treatment-related changes in 4 domains assessing both fine and gross motor function: balance (score 0 to 37), fine motor precision (score 0 to 41), manual dexterity (score 0 to 45), and running speed/agility (score 0 to 52). Higher scores indicate more motor proficiency; a positive change from baseline indicates improvement. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in BOT-2 was analyzed by GEE modeling based on observed data. The GEE model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable.
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
    End point values
    UX003 4 mg/kg
    Number of subjects analysed
    11 [8]
    Units: units on a scale
    least squares mean (standard error)
        Balance; n=6
    0.8 ± 0.46
        Fine motor precision; n=11
    -0.2 ± 0.23
        Manual dexterity; n=11
    0.2 ± 0.21
        Running speed and agility; n=5
    0.2 ± 0.12
    Attachments
    Untitled (Filename: BOT-2 statistical analyses.docx)
    Notes
    [8] - subjects who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale at UX003 Treatment Week 24

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    End point title
    Change From Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale at UX003 Treatment Week 24
    End point description
    The PedsQL 18-item scale is comprised of 3 dimensions: general fatigue (6 items), sleep/rest fatigue (6 items) and cognitive fatigue (6 items). Each item has a 5-point Likert response scale that is reverse scored and transformed to a 0 to 100 scale with higher scores indicating less fatigue. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in PedsQL total fatigue score was analyzed by GEE modeling based on observed data. The GEE model included all subjects who had non-missing baseline and ≥1 post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable.
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
    End point values
    UX003 4 mg/kg
    Number of subjects analysed
    12
    Units: units on a scale
        least squares mean (standard error)
    3.4 ± 2.64
    No statistical analyses for this end point

    Secondary: Percentage of Individual Clinical Response (ICR) Responders at UX003 Treatment Week 24

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    End point title
    Percentage of Individual Clinical Response (ICR) Responders at UX003 Treatment Week 24
    End point description
    Percentage of subjects who were ICR responders based on MID criteria at Week 24. At the Randomization visit, the physician queried the subject or parent/caregiver about signs and symptoms of MPS VII that interfered most with the subject’s daily life. Answers were mapped to an appropriate clinical outcome measure (e.g., difficulty walking could map to the 6MWT; breathing problems to FVC). The clinical outcome ranked with the highest impact on daily life that could be reliably completed by the subject and met a threshold level of impairment was selected as the ICR for that subject. ICR response was assessed based on a positive change (according to pre-specified MID criteria) of each subject’s ICR. Agresti–Coull confidence interval with nominal coverage ≥ 95%.
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
    End point values
    UX003 4 mg/kg
    Number of subjects analysed
    12
    Units: percentage of responders
        number (confidence interval 95%)
    25 (8.3 to 53.8)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Impactful Clinical Problem Total Score at UX003 Treatment Week 24

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    End point title
    Change From Baseline in Impactful Clinical Problem Total Score at UX003 Treatment Week 24
    End point description
    The 3 most impactful clinical problems as reported by the subject/parent/caregiver during the Clinical Problem Evaluation were scored on a Likert scale from 1 (very little problem) to 7 (an extreme amount) at randomization and post-randomization visits. At post-randomization visits, each clinical problem was again scored for impact on daily activities. Total scores ranged from 3 to 21; lower scores reflect less impact on daily life. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) The change from baseline up to UX003 Treatment Week 24 were analyzed by GEE modeling, including baseline value, and the post-UX003 initiation treatment week as a categorical variable. The covariance structure within subjects is assumed to be exchangeable.
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
    End point values
    UX003 4 mg/kg
    Number of subjects analysed
    12
    Units: units on a scale
        least squares mean (standard error)
    -1.2 ± 0.92
    Attachments
    Untitled (Filename: impactful clinical problems statistical analysis.docx)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety information was collected for all subjects who received any study drug from signing the informed consent form through 30 days after last dose of study drug. Mean treatment duration for UX003 was 36.0 weeks, and for placebo was 15.8 weeks.
    Adverse event reporting additional description
    Treatment-emergent adverse events (TEAEs) are presented. Given that the study has only has 12 subjects, and a by arm/group analysis would include no more than 3 subjects per arm/group, the TEAE summary was planned to present data by treatment only.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study, based on the blind-start design.

    Reporting group title
    UX003 Active Treatment
    Reporting group description
    Subjects received 4 mg/kg UX003 QOW per group assignment (based on the blind-start design) and were dosed through Week 46. All groups received a minimum of 24 weeks of treatment with UX003.

    Serious adverse events
    Placebo UX003 Active Treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 12 (16.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Craniocerebral injury
    Additional description: CTCAE grade 2 non-related craniocerebral injury as a result of falling off the bed. Computed tomography scan of the head did not show intracranial bleeding nor acute intracranial injury.
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactoid reaction
    Additional description: CTCAE grade 3 treatment-related anaphylactoid reaction secondary to an infusion rate error occurring during the first hour of UX003 administration.
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo UX003 Active Treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    12 / 12 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Immune system disorders
    Anaphylactoid reaction
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Seasonal allergy
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Infusion site extravasation
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 12 (33.33%)
         occurrences all number
    1
    4
    Oedema
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Catheter site bruise
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    3
    Chills
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Infusion site bruising
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Infusion site swelling
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Infusion site discomfort
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Post-traumatic stress disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Depression
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Excoriation
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 12 (8.33%)
         occurrences all number
    2
    2
    Contusion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Post-traumatic neck syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Tooth fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Craniocerebral injury
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Investigations
    Body temperature increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 9 (22.22%)
    3 / 12 (25.00%)
         occurrences all number
    2
    3
    Dyspnoea exertional
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Nasal obstruction
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Clonus
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Dysstasia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Eye disorders
    Eye pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    3
    Vomiting
         subjects affected / exposed
    2 / 9 (22.22%)
    3 / 12 (25.00%)
         occurrences all number
    3
    3
    Abdominal pain
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Abdominal pain lower
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    abdominal pain upper
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Abnormal faeces
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    Rectal haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    cheilosis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 12 (25.00%)
         occurrences all number
    2
    3
    Urticaria
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    Pruritus
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Rash macular
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Rash papular
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Skin ulcer
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    3 / 9 (33.33%)
    4 / 12 (33.33%)
         occurrences all number
    3
    5
    Arthralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Arthritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Joint range of motion decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    Joint swelling
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Decreased appetite
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 9 (33.33%)
    5 / 12 (41.67%)
         occurrences all number
    3
    6
    Ear infection
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    Cellulitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Oral herpes
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Rash pustular
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Otitis media acute
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Sep 2013
    The following parts of the protocol were updated: primary efficacy hypothesis and study objectives, investigational plan, efficacy measures, APRG safety reporting, statistical methodology, inclusion criteria, description of study drug. This amendment was made prior to the first patient consenting to the study.
    18 Sep 2014
    Dose selection was updated. This amendment was made prior to the first patient consenting to the study.
    07 Oct 2014
    The primary efficacy hypothesis and study objectives, efficacy measures and statistical analysis were updated. This amendment was made prior to the first patient consenting to the study.
    15 Dec 2014
    The drug concentration measurements, assessment of anti-drug antibodies, timing of assessments, relationship of adverse events to study drug and safety contact information were updated. This amendment was made after the first patient consented to the study.
    18 Apr 2016
    The urinary and serum GAG methodologies, record retention, complement level measurements, end of study definition, unblinding information and adverse event reporting were updated. This amendment was made after the first patient consented to the study.

    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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