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    Clinical Trial Results:
    A 24-month Multicenter, Open-label Phase II Trial Investigating the Safety and Efficacy of Repeated velmanase alfa (recombinant human alpha-mannosidase) Treatment in Pediatric Patients below 6 years of age with Alpha-Mannosidosis

    Summary
    EudraCT number
    2016-001988-36
    Trial protocol
    DK   DE   AT   FR   IT  
    Global end of trial date
    03 Jul 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Apr 2021
    First version publication date
    02 Apr 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-LMZYMAA1-08
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo 26/A, 43122, Parma, Italy,
    Public contact
    Chiara Franke, Clinical Project Manager, Chiesi Farmaceutici S.p.A., 0039 3451247439, c.franke.consultant@chiesi.com
    Scientific contact
    Chiara Franke, Clinical Project Manager, Chiesi Farmaceutici S.p.A., 0039 3451247439, c.franke.consultant@chiesi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001056-PIP02-12
    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
    01 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jul 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this trial were to evaluate safety and efficacy of repeated velmanase alfa intravenous (i.v.) infusions in paediatric subjects aged less than 6 years with alpha-mannosidosis.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines, and following all other requirements of local laws. Safety was assessed at every visit in terms of physical examinations, vital signs, adverse events (AEs), laboratory evaluations (haematology, biochemistry, coagulation, urinalysis) and monitoring of immunoglobulin (Ig)G immunogenicity. Adverse events and serious AEs were assessed at the baseline visit, all dose visits and in connection with the dosing performed at evaluation visits. Electrocardiograms and echocardiograms were recorded at the baseline visit, monitored during and after infusions at dose visits and recorded at the 12 and 24 months evaluation visits, and for the subject enrolled in France, also at the 40 months evaluation visit. Weight was recorded at baseline and every 4 weeks and used for dosage calculation. Head circumference and height were recorded at baseline and evaluation visits and growth velocity was assessed throughout the study. Vital signs (heart rate, systolic and diastolic blood pressure, respiratory rate and temperature) were monitored and the subject was observed for AEs during infusions of velmanase alfa, and during the observation period after dosing. At the discretion of the Investigator, a central venous catheter could be implanted to ease administration of velmanase alfa and facilitate other i.v. procedures during the study, and anaesthesia could be used during lumbar punctures, with prothrombin time or International Normalized Ratio being assessed prior to anaesthesia. Prior medications and medical/surgical history was recorded at baseline, concomitant medications and illnesses were assessed throughout the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Dec 2016
    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
    Austria: 1
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    5
    EEA total number of subjects
    5
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    5
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Overall, 6 subjects were screened according to inclusion/exclusion criteria, of these 5 subjects were enrolled in the study. Included subjects had to have a confirmed diagnosis of alpha-mannosidosis as defined by alpha-mannosidase activity in leukocytes or fibroblasts <10% of normal activity (historical data) and be aged <6 years at screening.

    Pre-assignment
    Screening details
    At the screening visit, eligible consenting subjects were identified, informed consent was obtained. The subject's ability to fulfil inclusion/exclusion criteria was evaluated, screening assessments were performed and the Investigator reviewed the results against the criteria. One subject (in Denmark) was a screen failure (exclusion criterion met).

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

    Arms
    Arm title
    Enrolled subjects
    Arm description
    This was an open-label trial where all enrolled subjects received once weekly administration of i.v. velmanase alfa (recombinant human alpha-mannosidase).
    Arm type
    Experimental

    Investigational medicinal product name
    Velmanase alfa
    Investigational medicinal product code
    CHFLMZYMAA1
    Other name
    Lamzede
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Velmanase alfa was administered as i.v. infusion once weekly at a dose of 1 mg/kg (weight recorded at first dose visit and every 4 weeks). Velmanase alfa is supplied as a freeze-dried sterile product in single use vials containing 10 mg of investigational medicinal product (IMP); each vial is to be reconstituted with 5.0 mL water for injection. Stability of the reconstituted product is 24 hours at 2-8°C and 10 hours at a maximum of 25°C. The solution should have reached room temperature prior to infusion. Vials were prepared as per the volume required for the dose of IMP and swirled with slow rotations for 10-15 seconds after reconstitution. The required volume was withdrawn into one or more large-dose syringes and an infusion set with a mounted filter was filled. The maximum infusion rate was 22.5 mL/hour. The last empty syringe was replaced with a syringe filled with 20 mL isotonic sodium chloride to infuse IMP left in the set. An i.v. catheter could be implanted to ease delivery.

    Number of subjects in period 1
    Enrolled subjects
    Started
    5
    Completed
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    -

    Reporting group values
    Overall trial Total
    Number of subjects
    5 5
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    5 5
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    0 0
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    4.30 (4.10 to 4.60) -
    Gender categorical
    Units: Subjects
        Female
    2 2
        Male
    3 3

    End points

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    End points reporting groups
    Reporting group title
    Enrolled subjects
    Reporting group description
    This was an open-label trial where all enrolled subjects received once weekly administration of i.v. velmanase alfa (recombinant human alpha-mannosidase).

    Primary: Number of subjects with infusion-related reactions

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    End point title
    Number of subjects with infusion-related reactions [1]
    End point description
    An AE was defined as any untoward medical occurrence in a subject administered a medicinal product and which did not necessarily have a causal relationship with this treatment. An infusion-related reaction (IRR) was defined as an AE which occurred during or after 2 hours of infusion of velmanase alfa and which was assessed by the Investigator as being infusion-related. Reported terms for AEs were coded using the Medical Dictionary for Regulatory Activities version 19.0. Absolute counts, percentages and number of events were presented for the number of subjects with at least one IRR, tabulated by System Organ Class and Preferred Term (PT). The number of subjects experiencing events by PT is presented. A subject who experienced multiple occurrences of an AE is presented only once in the respective subject count.
    End point type
    Primary
    End point timeframe
    Data for IRRs were collected from the first infusion, for the duration of the study.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the small sample size, as per protocol, data have been presented mainly through listings and when applicable only summarised, with no inferential statistics implemented.
    End point values
    Enrolled subjects
    Number of subjects analysed
    5 [2]
    Units: subjects
        Urticaria
    1
        Chills
    1
        Hyperthermia
    1
        Anal pruritus
    1
        Cyanosis
    1
    Notes
    [2] - Three subjects - 15 events: cyanosis-2, chills-3, hyperthermia-2, urticaria-5, anal pruritus-3.
    No statistical analyses for this end point

    Primary: Detection of anti-velmanase alfa IgG antibodies

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    End point title
    Detection of anti-velmanase alfa IgG antibodies [3]
    End point description
    Samples were collected for detection of anti-velmanase alfa IgG antibodies (ADAs) at baseline and every 4 weeks post-treatment for the first 3 months, then every 8 weeks. Additional samples could be collected at the Investigator's discretion when an IRR was suspected or as per clinical judgement. All IgG seropositive patients were tested for the presence of IgG neutralising antibodies to velmanase alfa. All subjects were ADA negative at study entry. The number of subjects who tested positive for ADAs during the study or remained negative throughout the study is presented. Of the subjects who seroconverted during the study, 2 subjects tested positive, then negative and then positive again during treatment; 2 subjects remained ADA positive from first detection until the end of the study.
    End point type
    Primary
    End point timeframe
    From baseline to the 24 months evaluation visit for 2 subjects, to 26 and a half months from baseline for 1 subject, to approximately 25 months from baseline for 1 subject, and to the 40 months evaluation visit for 1 subject.
    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: Due to the small sample size, as per protocol, data have been presented mainly through listings and when applicable only summarised, with no inferential statistics implemented.
    End point values
    Enrolled subjects
    Number of subjects analysed
    5 [4]
    Units: subjects
        Positive
    4
        Negative
    1
    Notes
    [4] - For ADA+ subjects, ADA concentrations ranged from below lower limit of quantification to 174 U/mL
    No statistical analyses for this end point

    Secondary: Change from baseline in serum oligosaccharide concentration (GlcNac[Man]2)

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    End point title
    Change from baseline in serum oligosaccharide concentration (GlcNac[Man]2)
    End point description
    Serum oligosaccharide concentration before and after treatment with velmanase alfa was an important biomarker used to assess the efficacy of velmanase alfa. Change from baseline in serum concentrations of serum oligosaccharides was analysed at the 6 months, 12 months, 18 months and 24 months evaluation visits, and for 1 patient, also at the 40 months evaluation visit. Change from baseline in serum concentration of GlcNac(Man)2 at the 24 months evaluation visit is reported.
    End point type
    Secondary
    End point timeframe
    Change from baseline to the 24 months evaluation visit
    End point values
    Enrolled subjects
    Number of subjects analysed
    4
    Units: micromole(s)/litre
        median (inter-quartile range (Q1-Q3))
    -7.10 (-10.40 to -5.05)
    No statistical analyses for this end point

    Secondary: Change from baseline in serum oligosaccharide concentrations (GlcNac[Man]3)

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    End point title
    Change from baseline in serum oligosaccharide concentrations (GlcNac[Man]3)
    End point description
    Serum oligosaccharide concentration before and after treatment with velmanase alfa was an important biomarker used to assess the efficacy of velmanase alfa. Change from baseline in concentration of serum oligosaccharides was analysed at 6 months, 12 months, 18 months, 24 months, and for 1 patient, also at 40 months. Change from baseline in serum concentration of GlcNac(Man)3 at 24 months is reported.
    End point type
    Secondary
    End point timeframe
    Change from baseline to the 24 months evaluation visit
    End point values
    Enrolled subjects
    Number of subjects analysed
    3
    Units: micromole(s)/litre
        median (inter-quartile range (Q1-Q3))
    -0.50 (-1.00 to -0.30)
    No statistical analyses for this end point

    Secondary: Number of stairs climbed during the 3-Minute Stair Climb Test

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    End point title
    Number of stairs climbed during the 3-Minute Stair Climb Test
    End point description
    The number of steps climbed in 3 minutes was measured at baseline and at evaluation visits at 6 months, 12 months, 18 months, 24 months and for 1 patient, at 40 months, to evaluate endurance. The 3-Minute Stair Climb Test is an indicator of functional exercise capacity. The test was administered by a certified physiotherapist in subjects from 4 years of age or when applicable according to the judgement of the Investigator. At each time point, 2 assessments were carried out on different days and the best value was evaluated for efficacy. The number of steps climbed in 3 minutes at baseline and 24 months is presented.
    End point type
    Secondary
    End point timeframe
    Baseline to 24 months evaluation visit.
    End point values
    Enrolled subjects
    Number of subjects analysed
    4
    Units: steps
    median (inter-quartile range (Q1-Q3))
        Baseline
    143.5 (115.5 to 162.0)
        24 months evaluation visit
    119.5 (64.0 to 164.0)
    No statistical analyses for this end point

    Secondary: Distance covered during the 6-Minute Walk Test

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    End point title
    Distance covered during the 6-Minute Walk Test
    End point description
    The 6-Minute Walk Test is an indicator of functional exercise capacity measuring the distance walked (in metres) on a flat, hard, surface in a period of 6 minutes. The test evaluates the global and integrated responses of all the systems involved during exercise including the pulmonary and cardiovascular systems, systemic circulation, peripheral circulation, blood, neuromuscular units and muscle metabolism. The test was administered by a certified physiotherapist in subjects from 4 years of age, or when applicable as per the Judgement of the Investigator, and performed in accordance with the American Thoracic Society standards. In order to evaluate endurance, the test was administered on two different days at each assessment, with best value evaluated for efficacy. Assessments were performed at baseline, 6 months, 12 months, 18 months, 24 months and for 1 patient, at 40 months. The distances walked in 6 minutes at baseline and 24 months are presented.
    End point type
    Secondary
    End point timeframe
    Baseline to the 24 months evaluation visit
    End point values
    Enrolled subjects
    Number of subjects analysed
    4 [5]
    Units: Steps
    median (inter-quartile range (Q1-Q3))
        Baseline
    278.5 (247.5 to 344.0)
        24 months evaluation visit
    265.0 (248.0 to 438.0)
    Notes
    [5] - 4 at baseline, 3 at 24 months
    No statistical analyses for this end point

    Secondary: Change from baseline in V Wave threshold (automatic auditory brainstem response audiometry)

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    End point title
    Change from baseline in V Wave threshold (automatic auditory brainstem response audiometry)
    End point description
    Automatic auditory brainstem response (A-ABR) audiometry is a neurologic test of auditory brainstem function in response to auditory stimuli (click or tone pip) transmitted from an acoustic transducer (insert earphone or headphone), which generate an evoked potential. Administration and interpretation are typically performed by an audiologist. The elicited waveform response is measured by surface electrodes typically placed at the vertex of the scalp and ear lobes. The amplitude (microvoltage) of the signal is averaged and charted against time (in milliseconds). The waveform peaks are labelled I-VII. These waveforms normally occur within a 10 millisecond time period after a click stimulus presented at high intensities (70-90 decibels above normal adult hearing level [dB nHL]). The V Wave threshold was measured for each ear at baseline and evaluation visits at 12 months, 24 months and for 1 patient, at 40 months. Change from baseline in V Wave threshold at 12 months is presented.
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months evaluation visit.
    End point values
    Enrolled subjects
    Number of subjects analysed
    4
    Units: dB nHL
    median (inter-quartile range (Q1-Q3))
        Right ear
    -10.0 (-17.5 to -2.5)
        Left ear
    -2.5 (-7.5 to 0.0)
    No statistical analyses for this end point

    Secondary: Change from baseline in serum immunoglobulin concentrations

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    End point title
    Change from baseline in serum immunoglobulin concentrations
    End point description
    Change from baseline in serum IgG, IgA and IgM concentrations were assessed at evaluation visits at 6 months, 12 months, 18 months, 24 months, and for 1 patient, at 40 months, for evaluation of subjects' immunological profiles. The change from baseline in serum Ig concentrations at 24 months is presented.
    End point type
    Secondary
    End point timeframe
    Baseline to the 24 months evaluation visit.
    End point values
    Enrolled subjects
    Number of subjects analysed
    4
    Units: gram(s)/litre
    median (inter-quartile range (Q1-Q3))
        IgG
    3.510 (1.985 to 5.195)
        IgA
    0.285 (0.110 to 0.795)
        IgM
    -0.160 (-0.195 to 0.265)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Data for AEs were collected from the time of informed consent, for the duration of the trial.
    Adverse event reporting additional description
    The Investigator collected all AEs from spontaneous reports of subjects, and by observation and routine open questioning. Only the treatment-emergent adverse events are reported.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Enrolled subjects
    Reporting group description
    This was an open-label trial where all enrolled subjects received once weekly administration of i.v. velmanase alfa (recombinant human alpha-mannosidase).

    Serious adverse events
    Enrolled subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Vascular fragility
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Henoch-Schonlein purpura
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cat scratch disease
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Enrolled subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 5 (80.00%)
         occurrences all number
    20
    Chills
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    2
    Hyperthermia
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    7
    Influenza like illness
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Breast swelling
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 5 (40.00%)
         occurrences all number
    2
    Ligament sprain
         subjects affected / exposed
    2 / 5 (40.00%)
         occurrences all number
    2
    Arthropod bite
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Eye injury
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Joint injury
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Limb injury
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Post lumbar puncture syndrome
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Traumatic haematoma
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Investigations
    Blood iron decreased
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    2
    Cardiac murmur
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 5 (80.00%)
         occurrences all number
    10
    Oropharyngeal pain
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Poor quality sleep
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Eye disorders
    Hypermetropia
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear haemorrhage
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Ear pain
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Hypoacusis
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Middle ear disorder
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Otorrhoea
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Tympanic membrane disorder
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    5 / 5 (100.00%)
         occurrences all number
    10
    Diarrhoea
         subjects affected / exposed
    3 / 5 (60.00%)
         occurrences all number
    4
    Dental caries
         subjects affected / exposed
    2 / 5 (40.00%)
         occurrences all number
    2
    Anal pruritus
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    3
    Dental cyst
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Tooth disorder
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Tooth loss
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Swelling face
         subjects affected / exposed
    2 / 5 (40.00%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Jaw disorder
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Infections and infestations
    Otitis media
         subjects affected / exposed
    4 / 5 (80.00%)
         occurrences all number
    9
    Rhinitis
         subjects affected / exposed
    3 / 5 (60.00%)
         occurrences all number
    10
    Conjunctivitis
         subjects affected / exposed
    2 / 5 (40.00%)
         occurrences all number
    4
    Ear infection
         subjects affected / exposed
    2 / 5 (40.00%)
         occurrences all number
    5
    Gastroenteritis
         subjects affected / exposed
    2 / 5 (40.00%)
         occurrences all number
    6
    Nasopharyngitis
         subjects affected / exposed
    2 / 5 (40.00%)
         occurrences all number
    9
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 5 (40.00%)
         occurrences all number
    5
    Bronchitis
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    2
    Dental fistula
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Febrile infection
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Gastrointestinal infection
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    3
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Tonsillitis
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Tooth infection
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    3

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Oct 2017
    Rationale was to update final selected laboratories and harmonise safety and pharmacokinetic timepoints. Details of new Clinical Project Manager, sites/countries, safety contacts, human blood bank and finalised central laboratories were updated. Time points for safety and pharmacokinetic assessments were harmonised; theoretical time point '22-hour post-infusion stop’ was substituted with ‘24-hour post-infusion stop’ for pharmacokinetic analysis. The following were specified in Sections: 1.2.5, 14 and Appendix (App) 1: the trial would be conducted in compliance with current ICH E6 GCP; 2.0: primary endpoints amended to delete detection of neutralising/inhibitory antibodies, Childhood Health Assessment Questionnaire deleted as assessment of quality of life via questionnaire to parents (secondary efficacy endpoints efficacy); other sections updated as required; 3.0: magnetic resonance spectroscopy, magnetic resonance imaging (MRI) and diffusion-MRI of the brain would be performed at baseline only if historical data in the previous 3 months were not available, allowing for retrospective MRI data to be used; other sections of the protocol updated and further details on these assessments also included in Section 8.8; 7: time points for pharmacokinetic assessments and the amount of blood/cerebrospinal fluid (CSF) to be collected for various analyses specified in text/trial flow chart; 7.1.2.1: assessments at baseline would be performed over 2 weeks (instead of 1 week) and alpha-mannosidase activity in leukocytes would be evaluated only if historical data were not available; 8.1: heading updated to specify that CSF oligosaccharides would also be assessed; 9.1.3.1: blood samples for clinical laboratory evaluations would be drawn 24 hours after infusion-stop (not after start of dosing); 10.1.5: requirement for the Investigator to consult with allergic reaction expert in case of severe IRR removed; 16.1, 16.2 added, 19 modified, App II included.
    21 Jan 2019
    New Section 8.10.2 was inserted, specifying details of planned additional blood sampling for bioanalytical assay development. The rationale was to develop a bioanalytical assay for the evaluation of the oligosaccharides content in the mononuclear cells aiming at following treatment response in a clinically relevant tissue. The Contract Research Organisation and Sponsor safety contact details were updated in Section 10.9.
    11 Apr 2019
    Details of the new Clinical Program Leader were provided. The laboratories involved in the additional blood sampling measurement mentioned in the previous version of the protocol were specified and details were updated in relevant sections of the protocol. Section 10.7 was updated regarding follow-up of AEs. Details on recording of AEs and reporting of SAEs to Sponsor were updated in Sections 10.8 and 10.9, respectively.
    27 Apr 2019
    Amendment number 1.0 (France) dated 12 February 2019 to Protocol Version 6.0 (dated 15 January 2019) was approved by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) on 27 April 2019. The rationale for the amendment was to extend the treatment for a further 12 months to cover the treatment for the subject enrolled in France until the availability of the drug on the French market. The IMP achieved reimbursement in France in December 2018 but was still not available on the market. Modification was required to the informed consent and the Case Report Form. Changes were made to sections of the protocol as appropriate to extend the duration of treatment for the French subject to 36 months, with addition of a final 36 months evaluation visit for performing efficacy assessments. For secondary endpoints it was specified that these included changes from baseline to 36 months for the French subject. The trial flow chart was updated to include additional dose visits, details of the evaluation visit and assessments at 36 months and specification of an end of trial visit for the French subject.
    24 Jun 2020
    Amendment number 2.0 (France) dated 17 April 2020 to Protocol Version 7.0 (dated 30 January 2020) was approved by the Comités de Protection des Personnes on 24 June 2020. The rationale for the amendment was to extend the treatment for a further 4 months to cover the treatment for the subject enrolled in France until the coronavirus-19 (COVID-19) emergency was over. Due to the pandemic the subject could not complete the 36 months evaluation visit, and the treatment was stopped from 16 March to 20 April 2020. The sponsor assumed that the COVID-19 restrictions would be over by August 2020 and thought to extend the treatment for the French subject for a further 4 months, and add a final evaluation visit at 40 months (Week 166 +/- 5 weeks) after at least 4 weeks of treatment resumption. Modification was required to the informed consent and the Case Report Form. Changes were made to sections of the protocol as appropriate to extend the duration of treatment for the French subject to 40 months, with addition of the final evaluation visit for performing efficacy assessments. For secondary endpoints it was specified that these included changes from baseline to 40 months for the French subject. The trial flow chart was updated to include additional dose visits, details of the evaluation visit and assessments at 40 months and specification of an end of trial visit for the French subject.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    16 Mar 2020
    Only the subject enrolled in France was affected. Due to the COVID-19 pandemic the treatment was stopped for the subject from 16 March to 20 April 2020. The treatment was extended for a further 4 months for this subject, and a final evaluation visit was planned after 40 months of treatment (after at least 4 weeks of treatment resumption).
    20 Apr 2020

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the COVID-19 pandemic, 1 patient missed 4 dose visits and performed 2 out of visit window, and the post-infusion observational period was reduced for some visits for 1 patient. Other patients had completed the study before.
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