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    Clinical Trial Results:
    A phase IIa study to investigate safety, Pharmacokinetics, and efficacy of odiparcil in patients 16 years and above with mucopolysaccharidosis (MPS) type VI.

    Summary
    EudraCT number
    		 2017-002158-35
    Trial protocol
    		 GB   DE   FR   PT  
    Global end of trial date
    22 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Aug 2020
    First version publication date
    16 Aug 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    IVA_01_ODI_HMPS_17_002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03370653
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Inventiva S.A.
    Sponsor organisation address
    50 rue de Dijon, Daix, France, 21121
    Public contact
    Mireille Tallandier, Inventiva S.A, +33 380 447 500, mireille.tallandier@inventivapharma.com
    Scientific contact
    Mireille Tallandier, Inventiva S.A, +33 380 447 500, mireille.tallandier@inventivapharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess the safety and efficacy of two doses of odiparcil in MPS VI patients and to provide evidence to enable the selection of the relevant dose of odiparcil for phase III study.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 In the ERT cohort, ERT (Enzyme Replacement Therapy) is background therapy.
    Evidence for comparator
    		 In the double blinded period, placebo is the comparator.
    Actual start date of recruitment
    30 Dec 2017
    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
    United Kingdom: 4
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Portugal: 3
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    3
    Adults (18-64 years)
    17
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment of patients started in December 2017 in the UK and last patient was recruited in May 2019 in France.

    Pre-assignment
    Screening details
    		 Main inclusion criteria: Male or female aged ≥16 years, with confirmed diagnosis of MPS VI For ERT cohort: patients under ERT for at least 6 months. For Non-ERT cohort: patients not receiving ERT due to discontinuation of ERT for more than 3 months, allergy to ERT, hematopoietic stem cell transplant or naïve to ERT.

    Period 1
    Period 1 title
    Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Data analyst, Carer, Assessor, Subject, Investigator, Monitor
    Blinding implementation details
    One of the 4 arms is an open-label arm with odiparcil 1000mg/day only.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ERT cohort - placebo
    Arm description
    		 Patients receiving ERT, randomized to receive placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo odiparcil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo of 250mg tablet of odiparcil

    Arm title
    		 ERT cohort - 500mg odiparcil
    Arm description
    		 Patients receiving ERT, randomized to 500mg odiparcil/day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Odiparcil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet of 250mg odiparcil to be taken orally twice a day

    Arm title
    		 ERT cohort - 1000mg odiparcil
    Arm description
    		 Patients receiving ERT, randomized to 1000 mg/day of odiparcil
    Arm type
    		 Experimental

    Investigational medicinal product name
    Odiparcil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 tablets of 250mg odiparcil to be taken orally twice a day.

    Arm title
    		 Non-ERT cohort - 1000mg odiparcil
    Arm description
    		 Patients not receiving ERT, open label arm with 1000 mg/day of odiparcil.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Odiparcil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 tablets of 250mg odiparcil to be taken orally twice a day.

    Number of subjects in period 1
    		ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Started
    5
    5
    5
    5
    Completed
    4
    3
    3
    3
    Not completed
    1
    2
    2
    2
         Adverse event, serious fatal
    1
    -
    -
    -
         Adverse event, non-fatal
    -
    2
    2
    2
    Period 2
    Period 2 title
    Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ERT cohort - placebo
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 ERT cohort - 500mg odiparcil
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 ERT cohort - 1000mg odiparcil
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Non-ERT cohort
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort
    Started
    4
    3
    3
    3
    Completed
    4
    3
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ERT cohort - placebo
    Reporting group description
    		 Patients receiving ERT, randomized to receive placebo

    Reporting group title
    ERT cohort - 500mg odiparcil
    Reporting group description
    		 Patients receiving ERT, randomized to 500mg odiparcil/day.

    Reporting group title
    ERT cohort - 1000mg odiparcil
    Reporting group description
    		 Patients receiving ERT, randomized to 1000 mg/day of odiparcil

    Reporting group title
    Non-ERT cohort - 1000mg odiparcil
    Reporting group description
    		 Patients not receiving ERT, open label arm with 1000 mg/day of odiparcil.

    Reporting group values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil Total
    Number of subjects
    		 5 5 5 5 20
    Age categorical
    Patients 16 years old and above
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 2 0 1 0 3
        Adults (18-64 years)
    		 3 5 4 5 17
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
        Adolescents
    		 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 2 3 2 2 9
        Male
    		 3 2 3 3 11
    Subject analysis sets

    Subject analysis set title
    Full analysis set population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) population included all randomised patients in double-blind cohort or included in open-label cohort, receiving at least one dose of study treatment.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Patients receiving at least one dose of study treatment.

    Subject analysis set title
    Patients completing the study
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients from the Full Analysis Set having completed the Week 26 visit.

    Subject analysis set title
    Preliminary Assessment Period Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    2 patients receiving ERT were included in the PSA period, an open-label escalating dose part of the study. Both patients received odiparcil 500mg per day for 7 days, then odiparcil 1000mg per day for 7 days. Both patients were then included in the Core study, which is the baseline for the analysis.

    Subject analysis sets values
    		 Full analysis set population Safety population Patients completing the study Preliminary Assessment Period Subjects
    Number of subjects
    20
    20
    13
    2
    Age categorical
    Patients 16 years old and above
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    3
    3
    3
    0
        Adults (18-64 years)
    17
    17
    10
    2
        From 65-84 years
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
        Adolescents
    0
    0
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
    9
    9
    4
        Male
    11
    11
    9

    End points

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    End points reporting groups
    Reporting group title
    ERT cohort - placebo
    Reporting group description
    		 Patients receiving ERT, randomized to receive placebo

    Reporting group title
    ERT cohort - 500mg odiparcil
    Reporting group description
    		 Patients receiving ERT, randomized to 500mg odiparcil/day.

    Reporting group title
    ERT cohort - 1000mg odiparcil
    Reporting group description
    		 Patients receiving ERT, randomized to 1000 mg/day of odiparcil

    Reporting group title
    Non-ERT cohort - 1000mg odiparcil
    Reporting group description
    		 Patients not receiving ERT, open label arm with 1000 mg/day of odiparcil.
    Reporting group title
    ERT cohort - placebo
    Reporting group description
    		 -

    Reporting group title
    ERT cohort - 500mg odiparcil
    Reporting group description
    		 -

    Reporting group title
    ERT cohort - 1000mg odiparcil
    Reporting group description
    		 -

    Reporting group title
    Non-ERT cohort
    Reporting group description
    		 -

    Subject analysis set title
    Full analysis set population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) population included all randomised patients in double-blind cohort or included in open-label cohort, receiving at least one dose of study treatment.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Patients receiving at least one dose of study treatment.

    Subject analysis set title
    Patients completing the study
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients from the Full Analysis Set having completed the Week 26 visit.

    Subject analysis set title
    Preliminary Assessment Period Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    2 patients receiving ERT were included in the PSA period, an open-label escalating dose part of the study. Both patients received odiparcil 500mg per day for 7 days, then odiparcil 1000mg per day for 7 days. Both patients were then included in the Core study, which is the baseline for the analysis.

    Primary: Total distance walk: absolute change in 6-Minute Walk test from reference

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    End point title
    		 Total distance walk: absolute change in 6-Minute Walk test from reference [1]
    End point description
    The 6-minute walk test (6MWT) measures the distance that a person can walk quickly in six minutes and it was performed as a measure of endurance.
    End point type
    Primary
    End point timeframe
    From V0 to V7
    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: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: meter
        arithmetic mean (standard deviation)
    -39.88 ( 58.14 )
    8.00 ( 15.72 )
    -35.00 ( 34.77 )
    5.17 ( 21.13 )
    No statistical analyses for this end point

    Primary: Time to complete the test dominant hand: 9-Hole Peg Test absolute change from reference

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    End point title
    		 Time to complete the test dominant hand: 9-Hole Peg Test absolute change from reference [2]
    End point description
    This test is a measure of dexterity.
    End point type
    Primary
    End point timeframe
    V0 to V7
    Notes
    [2] - 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: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort
    Number of subjects analysed
    4
    3
    2
    2
    Units: second
        median (inter-quartile range (Q1-Q3))
    -2.48 (-6.66 to 72.89)
    -2.05 (-2.55 to 2.00)
    -0.43 (-1.50 to 0.65)
    24.2 (-3.00 to 51.40)
    No statistical analyses for this end point

    Primary: Shoulder-Range Of Motion on left shoulder: absolute change from reference

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    End point title
    		 Shoulder-Range Of Motion on left shoulder: absolute change from reference [3]
    End point description
    Range of Motion of the shoulder: both active and passive measurements of the shoulder (flexion, extension, abduction, croos-body-addution), executed with a goniometer by a single operator per site. Defined as sum of passive abduction and flexion.
    End point type
    Primary
    End point timeframe
    V0 to V7
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: degree
        arithmetic mean (standard deviation)
    15.00 ( 44.49 )
    4.67 ( 9.50 )
    -26.50 ( 48.51 )
    12.67 ( 24.96 )
    No statistical analyses for this end point

    Primary: Shoulder-Range Of Motion on right shoulder: absolute change from reference

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    End point title
    		 Shoulder-Range Of Motion on right shoulder: absolute change from reference [4]
    End point description
    End point type
    Primary
    End point timeframe
    V0 to V7
    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: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: degree
        arithmetic mean (standard deviation)
    4.38 ( 33.06 )
    -1.83 ( 25.18 )
    -15.67 ( 16.51 )
    11.83 ( 33.36 )
    No statistical analyses for this end point

    Primary: BPI Pain right now: absolute change from reference

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    End point title
    		 BPI Pain right now: absolute change from reference [5]
    End point description
    The Brief Pain Inventory (BPI) - Short Form (BPI-sf) is a 9-item self-administered questionnaire used to evaluate the severity of a patient's pain and the impact of this pain on the patient's daily functioning. The patients were asked to rate their worst, least, average, and current pain intensity, list current treatments and their perceived effectiveness, and rate the degree that pain interferes with general activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment of life on a 10-point scale.
    End point type
    Primary
    End point timeframe
    V0 to V7
    Notes
    [5] - 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: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: unit(s)
        arithmetic mean (standard deviation)
    -0.75 ( 1.66 )
    -0.50 ( 0.50 )
    0.67 ( 2.02 )
    -3.00 ( 0.87 )
    No statistical analyses for this end point

    Primary: BPI pain interference: absolute change from reference

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    End point title
    		 BPI pain interference: absolute change from reference [6]
    End point description
    The Brief Pain Inventory (BPI) - Short Form (BPI-sf) is a 9-item self-administered questionnaire used to evaluate the severity of a patient's pain and the impact of this pain on the patient's daily functioning. The patients were asked to rate their worst, least, average, and current pain intensity, list current treatments and their perceived effectiveness, and rate the degree that pain interferes with general activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment of life on a 10-point scale.
    End point type
    Primary
    End point timeframe
    V0 to V7
    Notes
    [6] - 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: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: unit(s)
        arithmetic mean (standard deviation)
    -1.84 ( 1.12 )
    -0.60 ( 0.27 )
    1.19 ( 3.94 )
    -1.52 ( 2.04 )
    No statistical analyses for this end point

    Primary: Forced Vital Capacity: relative change from reference

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    End point title
    		 Forced Vital Capacity: relative change from reference [7]
    End point description
    End point type
    Primary
    End point timeframe
    V0 to V7
    Notes
    [7] - 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: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    2
    Units: litre(s)
        arithmetic mean (standard deviation)
    -5.62 ( 9.03 )
    2.39 ( 2.58 )
    5.14 ( 3.50 )
    9.41 ( 13.30 )
    No statistical analyses for this end point

    Primary: Left Carotida Intima-Media Thickness: absolute change from baseline

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    End point title
    		 Left Carotida Intima-Media Thickness: absolute change from baseline [8]
    End point description
    Carotida intima-media thickness (CIMT) measure with ultrasound is widely used and well validated imaging technic to assess arteriosclerosis.
    End point type
    Primary
    End point timeframe
    V0 to V7
    Notes
    [8] - 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: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: millimeter(s)
        median (inter-quartile range (Q1-Q3))
    0.02 (-0.09 to 0.04)
    0.03 (-0.02 to 0.04)
    0.00 (-0.14 to 0.06)
    -0.07 (-0.10 to 0.12)
    No statistical analyses for this end point

    Primary: Righy Carotida Intima-Media Tickness: absolute change from baseline

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    End point title
    		 Righy Carotida Intima-Media Tickness: absolute change from baseline [9]
    End point description
    Carotid intima-media thickness (CIMT) measure with ultrasound is widely used and well validated imaging technic to assess arteriosclerosis.
    End point type
    Primary
    End point timeframe
    V0 to V7
    Notes
    [9] - 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: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: millimeter(s)
        median (inter-quartile range (Q1-Q3))
    0.01 (-0.03 to 0.02)
    0.03 (0.03 to 0.06)
    -0.05 (-0.23 to 0.07)
    0.01 (-0.04 to 0.13)
    No statistical analyses for this end point

    Primary: Visual acuity on left eye: absolute change from baseline

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    End point title
    		 Visual acuity on left eye: absolute change from baseline [10]
    End point description
    End point type
    Primary
    End point timeframe
    V0 to V7
    Notes
    [10] - 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: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    3
    3
    2
    2
    Units: LogMar
        arithmetic mean (standard deviation)
    -0.07 ( 0.06 )
    0.10 ( 0.10 )
    0.00 ( 0.00 )
    0.00 ( 0.00 )
    No statistical analyses for this end point

    Primary: Visual acuity on right eye: absolute change from baseline

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    End point title
    		 Visual acuity on right eye: absolute change from baseline [11]
    End point description
    End point type
    Primary
    End point timeframe
    V0 to V7
    Notes
    [11] - 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: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    2
    2
    2
    Units: LogMar
        arithmetic mean (standard deviation)
    0.04 ( 0.18 )
    0.15 ( 0.07 )
    0.20 ( 0.28 )
    0.00 ( 0.14 )
    No statistical analyses for this end point

    Primary: Corneal opacification measure on left eye: absolute change from baseline

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    End point title
    		 Corneal opacification measure on left eye: absolute change from baseline [12]
    End point description
    End point type
    Primary
    End point timeframe
    V0 to V7
    Notes
    [12] - 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: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    3
    2
    1
    2
    Units: number
        arithmetic mean (standard deviation)
    -7.67 ( 3.56 )
    -1.02 ( 14.15 )
    -4.99 ( 0.00 )
    -2.15 ( 3.04 )
    No statistical analyses for this end point

    Primary: Corneal opacification measure on right eye: absolute change from baseline

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    End point title
    		 Corneal opacification measure on right eye: absolute change from baseline [13]
    End point description
    End point type
    Primary
    End point timeframe
    V0 to V7
    Notes
    [13] - 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: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    2
    2
    3
    Units: number
        arithmetic mean (standard deviation)
    -2.61 ( 5.54 )
    -5.55 ( 11.31 )
    -10.04 ( 3.72 )
    -9.25 ( 14.08 )
    No statistical analyses for this end point

    Primary: Zarit caregiver burden interview results at visit 7:Global score: absolute change from reference

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    End point title
    		 Zarit caregiver burden interview results at visit 7:Global score: absolute change from reference [14]
    End point description
    End point type
    Primary
    End point timeframe
    V0 to V7
    Notes
    [14] - 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: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    3
    2
    3
    3
    Units: unit(s)
        arithmetic mean (standard deviation)
    -4.83 ( 0.76 )
    -2.25 ( 2.47 )
    -2.00 ( 2.18 )
    5.17 ( 11.25 )
    No statistical analyses for this end point

    Primary: Fatigue severity scale results at visit 7: Global score: absolute change from reference

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    End point title
    		 Fatigue severity scale results at visit 7: Global score: absolute change from reference [15]
    End point description
    End point type
    Primary
    End point timeframe
    V0 to V7
    Notes
    [15] - 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: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: unit(s)
        arithmetic mean (standard deviation)
    -5.50 ( 7.88 )
    -2.50 ( 6.06 )
    -0.67 ( 3.06 )
    -3.17 ( 17.48 )
    No statistical analyses for this end point

    Primary: EQ-5D-5L results at visit 7: Global Health

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    End point title
    		 EQ-5D-5L results at visit 7: Global Health [16]
    End point description
    End point type
    Primary
    End point timeframe
    V0 to V7
    Notes
    [16] - 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: Because of the very low number of patients, it was expected to have difficulties to detect significant differences using usual statistical tests, but only signals of effect / trends. P-values (Fisher's exact or Chi-square tests) of the difference were provided in the CSR for information purposes but are not part of this report.
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: unit(s)
        arithmetic mean (standard deviation)
    70.50 ( 18.65 )
    63.33 ( 5.77 )
    53.33 ( 17.56 )
    66.67 ( 15.28 )
    No statistical analyses for this end point

    Post-hoc: Evaluation of 6-Minute Walk Test made by the external representatives of the Trial Steering Committee

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    End point title
    		 Evaluation of 6-Minute Walk Test made by the external representatives of the Trial Steering Committee
    End point description
    This test measures the distance that a person can walk in 6 minutes. Evaluation made by the TSC external representatives that was based on relative change of 6MWT between visit 7 (week 26) and reference
    End point type
    Post-hoc
    End point timeframe
    vo to v7
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: na
        Improved
    1
    1
    0
    0
        Stable/Slightly improved
    0
    0
    0
    0
        Stable
    1
    2
    0
    2
        Slightly worsened/Stable
    1
    0
    0
    0
        Worsened
    1
    0
    3
    1
    No statistical analyses for this end point

    Post-hoc: Evaluation of 9-Hole Peg Test for the dominant hand made by the external representatives of the Trial Steering Committee

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    End point title
    		 Evaluation of 9-Hole Peg Test for the dominant hand made by the external representatives of the Trial Steering Committee
    End point description
    This test is a measure of dexterity.
    End point type
    Post-hoc
    End point timeframe
    V0 to V7
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: NA
        Improved
    3
    2
    0
    0
        Stable/Slightly improved
    0
    0
    0
    1
        Stable
    0
    0
    1
    0
        Slightly worsened/Stable
    0
    0
    1
    0
        Worsened
    1
    1
    0
    1
        Not assessable
    0
    0
    1
    1
    No statistical analyses for this end point

    Post-hoc: Evaluation of Shoulder Range Of Motion made by the external representative of the Trial Steering Committee

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    End point title
    		 Evaluation of Shoulder Range Of Motion made by the external representative of the Trial Steering Committee
    End point description
    End point type
    Post-hoc
    End point timeframe
    V0 to V7
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: NA
        Improved
    2
    0
    0
    2
        Stable/Slightly improved
    0
    1
    0
    0
        Stable
    0
    1
    1
    0
        Slighlty worsened/Stable
    1
    1
    1
    0
        Worsened
    1
    0
    1
    1
    No statistical analyses for this end point

    Post-hoc: Evaluation of pain made by the external representatives of the Trial Steering Committee

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    End point title
    		 Evaluation of pain made by the external representatives of the Trial Steering Committee
    End point description
    Pain from BPI questionnaire, intensity and interference, was assessed by the TSC external representatives on a case-by-case basis. Results were presented to the TSC external representatives as absolute change.
    End point type
    Post-hoc
    End point timeframe
    V0 to V7
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: NA
        Improved
    2
    0
    0
    2
        Stable/Slighlty improved
    0
    1
    1
    1
        Stable
    2
    2
    1
    0
        Slightly worsened/Stable
    0
    0
    0
    0
        Worsened
    0
    0
    1
    0
    No statistical analyses for this end point

    Post-hoc: Evaluation of Forced Vital Capacity made by the external representatives of the Trial Steering Committee

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    End point title
    		 Evaluation of Forced Vital Capacity made by the external representatives of the Trial Steering Committee
    End point description
    End point type
    Post-hoc
    End point timeframe
    V0 to V7
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: NA
        Improved
    0
    0
    0
    1
        Stable/Slightly improved
    0
    1
    2
    0
        Stable
    2
    2
    1
    1
        Slightly worsened/Stable
    1
    0
    0
    0
        Worsened
    1
    0
    0
    0
        Not assessable
    0
    0
    0
    1
    No statistical analyses for this end point

    Post-hoc: Evaluation of Carotid Intima-Media Thickness made by the cardiovascular expert

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    End point title
    		 Evaluation of Carotid Intima-Media Thickness made by the cardiovascular expert
    End point description
    Carotid intima-media thickness (CIMT) measure with ultrasound is widely used and well validated imaging technic to assess arteriosclerosis.
    End point type
    Post-hoc
    End point timeframe
    V0 to V7
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: NA
        Improved
    1
    0
    1
    0
        Slightly improved/Stable
    0
    0
    0
    1
        Stable
    2
    2
    1
    1
        Stable/Slightly worsened
    1
    1
    1
    1
        Worsened
    0
    0
    0
    0
    No statistical analyses for this end point

    Post-hoc: Evaluation of cardiac parameters made by the cardiovascular expert

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    End point title
    		 Evaluation of cardiac parameters made by the cardiovascular expert
    End point description
    The echocardiogram parameters reviewed by the expert were intraventricular septal thickness at end diastole, left ventricular end-diastolic diameter and posterior wall thickness at end diastole.
    End point type
    Post-hoc
    End point timeframe
    V0 to V7
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: NA
        Improved
    0
    0
    1
    0
        Stable/Slightly improved
    1
    2
    1
    0
        Stable
    3
    0
    0
    1
        Slightly worsened/Stable
    0
    1
    1
    1
        Worsened
    0
    0
    0
    1
    No statistical analyses for this end point

    Post-hoc: Evaluation of audiology parameters made by the audiology expert

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    End point title
    		 Evaluation of audiology parameters made by the audiology expert
    End point description
    End point type
    Post-hoc
    End point timeframe
    V0 to V7
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: NA
        Improved
    0
    0
    0
    0
        Stable/Slightly improved
    0
    0
    0
    0
        Stable
    4
    2
    3
    2
        Slightly worsened/Stable
    0
    0
    0
    0
        Worsened
    0
    0
    0
    0
        Not assessable
    0
    1
    0
    1
    No statistical analyses for this end point

    Post-hoc: Evaluation of ophthalmology assessment made by the ophthalmology experts

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    End point title
    		 Evaluation of ophthalmology assessment made by the ophthalmology experts
    End point description
    End point type
    Post-hoc
    End point timeframe
    V0 to V7
    End point values
    		 ERT cohort - placebo ERT cohort - 500mg odiparcil ERT cohort - 1000mg odiparcil Non-ERT cohort - 1000mg odiparcil
    Number of subjects analysed
    4
    3
    3
    3
    Units: NA
        Improved
    0
    1
    1
    0
        Slightly improved/Stable
    1
    0
    0
    0
        Stable
    3
    0
    2
    2
        Stable/Slightly worsened
    0
    1
    0
    0
        Worsened
    0
    0
    0
    0
        Not assessable
    0
    1
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    December 2017 to October 2019
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    ERT cohort: ERT + Placebo
    Reporting group description
    		 -

    Reporting group title
    ERT cohort: ERT + odiparcil 500mg/day
    Reporting group description
    		 -

    Reporting group title
    ERT cohort: ERT + odiparcil 1000mg/day
    Reporting group description
    		 -

    Reporting group title
    Non-ERT cohort: odiparcil 1000mg/day
    Reporting group description
    		 -

    Reporting group title
    PSA period: odiparcil 500mg or 1000mg/day
    Reporting group description
    		 -

    Serious adverse events
    		 ERT cohort: ERT + Placebo ERT cohort: ERT + odiparcil 500mg/day ERT cohort: ERT + odiparcil 1000mg/day Non-ERT cohort: odiparcil 1000mg/day PSA period: odiparcil 500mg or 1000mg/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 5 (40.00%)
    3 / 5 (60.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    1
    0
    0
    0
    0
    Vascular disorders
    Venous occlusion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumopathy
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 ERT cohort: ERT + Placebo ERT cohort: ERT + odiparcil 500mg/day ERT cohort: ERT + odiparcil 1000mg/day Non-ERT cohort: odiparcil 1000mg/day PSA period: odiparcil 500mg or 1000mg/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    5 / 5 (100.00%)
    5 / 5 (100.00%)
    5 / 5 (100.00%)
    1 / 2 (50.00%)
    Surgical and medical procedures
    Central venous catheter removal
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Tooth extraction
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 5 (40.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Malaise
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    1
    0
    0
    Cough
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Investigations
    Protein urine present
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 5 (40.00%)
    2 / 5 (40.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    2
    1
    0
    Activated partial thromboplastin time prolonged
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
    2 / 5 (40.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    2
    3
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Body temperature decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Coagulation test abnormal
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Transaminases increased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Laboratory test interference
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    International normalised ratio abnormal
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Limb injury
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Neck injury
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Tracheostomy malfunction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Post-traumatic pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Migraine
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Migraine with aura
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    2
    0
    0
    0
    1
    Presyncope
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Ear and labyrinth disorders
    Middle ear adhesions
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Otorrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Tympanic membrane perforation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Vertigo
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    2 / 5 (40.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Rash
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Eczema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Miliaria
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Crystalluria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Hydronephrosis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Micturition urgency
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 5 (40.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Ear infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Folliculitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Laryngitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Tracheobronchitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Iron deficiency
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Sep 2017
    - Specification of highly effective contraception in accordance with Clinical Trial Facilitation Group document for clarification of contraception in inclusion criteria #7 and in footer related to exclusion criteria #13 and #14 - Addition of EudraCT Number on study treatment labels UK only.
    20 Feb 2018
    - Revision of inclusion criteria for patients not treated with ERT - Specifications added to exclusion criteria # 9 and #10 for patients included in PSA. - Revision of calendar - Changes in study design : both patients receiving ERT and patients not receiving ERT were able to participate in PSA - Addition of sample collections for the analysis of bone markers 25-Hydroxy-Vitamin D and TRACP 5b - Clarification of the list of criteria for permanent treatment discontinuation (section 7.1.3) - Revision of definitions for AE causality rate, action taken and outcome in accordance with CDISC standards UK only.
    30 May 2018
    - Shortening of follow-up period to 4 weeks - Specification of definition for women with childbearing potential - Revision of inclusion criterion #7 to specify a double method of contraception is required - Justification for inclusion of patients below 18 years of age. France only.
    12 Jun 2018
    - Change of randomisation methodology due to the addition of new investigational sites. - Exclusion of patients below 18 years of age - Revision of inclusion criterion #4 to clarify that uGAG criterion is based on historical data - Addition of a new PD evaluation: TGA following scientific advice meeting wih Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) Germany only.
    20 Jul 2018
    - Specification of definition for women with childbearing potential (UK) - Revision of inclusion criterion #4 to clarify that uGAG criteria was based on historical data (France and UK) - Revision of inclusion criterion #7 to specify a double method of contraception is required (UK) - Justification for inclusion of patients below 18 years of age (UK) - Shortening of follow-up period to 4 weeks (UK) - Harmonisation of label description (France and UK) - Addition of investigational sites in France and Portugal (UK) - Addition of investigational sites in Portugal (France) - Change in randomisation methodology (France and UK) - Clarification of study treatment dispensation during PSA period (France and UK) - Addition of a new pharmacodynamics evaluation: TGA (France and UK)
    10 Dec 2018
    - Revision of exclusion criterion #2 to clarify severe respiratory insufficiency and to add severe renal insufficiency PT only.
    18 Jun 2019
    - Section 4.1 Study design: revision of patient number from 24 to 20 (and throughout the document) due to unavailability of new patients for recruitment - Section 5.2 Exclusion criteria: clarification of exclusion criterion #10 with Investigator’s judgment addition for aPTT and TT values - Section 5.4 Strategies for recruitment and retention: clarification - Section 6.2.2 IMP packaging and labelling: update of label template - Section 9.7 Guidelines for management of specific coagulation abnormalities: additional coagulation tests - Section 9.11.2 Laboratory Tests: clarification of the scope of the unscheduled laboratory tests - Section 9.11.5 Proteinuria: new section - Section 10.6 Ophthalmology assessments: clarification of non-compulsory assessments - Update of monitoring and data management service provider (CRO), update of Sponsor’s representatives

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    23 May 2019
    For the 2 SUSARs Proteinuria (Investigator’s description “laboratory test interference (proteinuria)”), the relationship to the IMP was considered by the Investigator as possibly related but assessed by the Sponsor as not related for Proteinuria and definitely related for Laboratory test interference. These 2 SUSARs constituted a New Fact that was appropriately reported to all involved CAs and IECs of the participating countries. Following the receipt on 16 May 2019 of those 2 SUSARs Proteinuria, an ad hoc DSMB meeting was held on 20 May 2019 during which the Sponsor communicated the clinical findings to DSMB members and study Investigators, and reminded them of the pre-clinical findings, during the open session. As a conclusion of this previous development program: •No AE Proteinuria was reported across phase 1 studies and •In the vast majority of subjects, there was no urinary abnormal laboratory values in phase 2 studies. All available clinical and biological study data were reviewed by the DSMB during the closed session. A second ad hoc DSMB meeting was held in a closed session on 22 May 2019 and the DSMB recommendations were received on 23 May 2019 and were as follows: •Continuation in the core study with modifications and/or additional expert review: Request additional expert review to understand the mechanistic basis for proteinuria, potential long term consequences and the methodology undertaken for measurement of proteinuria Discuss with the Investigators and DSMB the expert opinion, and the potential for unblinding on trials outcomes •Temporary suspension of study enrolment (submitted as an USM to all CAs and IECs of the participating countries on 24 May 2019) On 27 Oct. 2019, DSMB issued an addendum to the 03 Jul 2019 recommendations with details on methods leading to laboratory interference, and on the cases of SUSARs Proteinuria:It is the opinion of the DSMB that the proteinuria reported as SUSAR has been adequately investigated.
    -

    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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