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    Clinical Trial Results:
    A multi-center, un-controlled, open-labeled trial of the long-term safety of velmanase alfa aftercare treatment of subjects with alpha-Mannosidosis

    Summary
    EudraCT number
    2013-000336-97
    Trial protocol
    DK   FR  
    Global end of trial date
    30 Sep 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    21 May 2023
    First version publication date
    21 May 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    rhLAMAN-07
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01908712
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    EudraCT: 2013-000336-97
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy, 43122
    Public contact
    Chiesi Clinical Trial, Chiesi Farmaceutici S.p.A, 0039 05212791, clinicaltrials_info@chiesi.com
    Scientific contact
    Chiesi Clinical Trial, Chiesi Farmaceutici S.p.A, 0039 05212791, clinicaltrials_info@chiesi.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Apr 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective: evaluation of safety of repeated velmanase alfa intravenous (i.v.) treatment of subjects with alpha-mannosidosis. Secondary objectives: evaluating long-term efficacy of velmanase alfa on endurance (6-Minute Walk Test (6MWT), 3-Minute Stair Climb Test (3MSCT)), pulmonary function, serum oligosaccharides, hearing, cognitive development (Leiter International Performance Scale - Revised), motor proficiency (Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition), quality of life (Childhood health Assessment Questionnaire (CHAQ), EuroQoL-5 Dimensions 5-Levels Questionnaire), cerebrospinal fluid (CSF) and 24-hour urine oligosaccharides, central nervous system involvement (imaging and CSF biomarkers (tubulin associated unit, neurofilament light and glial fibrillary acidic proteins)) and in vivo biological activity; evaluating pharmacokinetics; monitoring long-term safety profile including immunogenicity (anti-immunoglobulin (Ig)G) anti-drug antibodies (ADAs)).
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and following all other requirements of local laws. Subjects who had enrolled in earlier velmanase alfa trials (rhLAMAN-02/-03/-04, rhLAMAN-05 and rhLAMAN-08) and those not previously enrolled in a velmanase alfa trial were enrolled. Adverse events including infusion-related reactions were collected at every visit. Other safety assessments (performed as per the trial flow chart) including laboratory evaluations (haematology, biochemistry, urinalysis, coagulation tests), physical examination, recording of vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate and body temperature), tests for ADAs and neutralising antibodies (every 12 weeks) and serum IgG/IgM/IgA (every 24 weeks). Electrocardiograms (ECGs) and echocardiograms were recorded at a comprehensive evaluation visit (CEV) performed by 7 subjects who had enrolled in earlier trials. At the first dose visit for subjects not previously enrolled in a velmanase alfa trial, vital signs were monitored immediately prior to infusion, every 30 minutes (±5 minutes) during infusion and during the observation period of 2 hours post-infusion. At other dosing visits, medical personnel continuously observed subjects until 1 hour post-infusion; vital signs were monitored at the Investigator's discretion; and observation periods were prolonged if required. Medical/surgical history was recorded at screening. Concomitant medications and illnesses were collected throughout the trial. During the coronavirus disease 2019 (COVID-19) pandemic, a contingency plan was developed for protection of subjects in treatment phase and appropriate mitigation actions were adopted according to local regulations. These included implementation of a home infusion programme for suitable subjects (as determined by the Investigator) with infusions administered by specialised nurses.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Sep 2013
    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
    France: 13
    Worldwide total number of subjects
    13
    EEA total number of subjects
    13
    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)
    6
    Adolescents (12-17 years)
    3
    Adults (18-64 years)
    4
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Initially, only subjects who had completed rhLAMAN-04 or rhLAMAN-05 trials were eligible for inclusion and 7 subjects were enrolled. Further to protocol amendments, a subject who had completed the rhLAMAN-08 trial and 5 subjects not previously enrolled in a velmanase alfa trial with confirmed diagnosis of alpha-mannosidosis were later enrolled.

    Pre-assignment
    Screening details
    An informed consent from subjects/their legally authorised guardians was obtained prior to any trial-related procedures. Inclusion/exclusion criteria were checked, medical/surgical history and concomitant medications and illnesses were collected, demographics were recorded and a serum pregnancy test was performed as applicable.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable, open-label trial.

    Arms
    Arm title
    Enrolled subjects
    Arm description
    This was an open-label trial where all enrolled subjects received once weekly i.v. administration of the investigational medicinal product (IMP) velmanase alfa (recombinant human alpha-mannosidase). All enrolled subjects were included in the Full Analysis Set and the Safety Analysis Set.
    Arm type
    Experimental

    Investigational medicinal product name
    Velmanase alfa
    Investigational medicinal product code
    CHFLMZYM
    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 for subjects not previously enrolled in a velmanase alfa trial, and every 4 weeks for all subjects). An i.v. catheter could be implanted to ease delivery. The IMP is supplied as a sterile freeze-dried product in single use vials containing 10 mg, each to be reconstituted with 5.0 mL sterile water for injection. Stability of the reconstituted product is 24 hours at 5°C±3°C and 10 hours at a maximum of 25°C. The solution should reach room temperature prior to infusion. Vials were prepared as per the volume required for the dose and swirled with slow rotations for 10-15 seconds after reconstitution, required volume was withdrawn into one or more large-dose syringes and an infusion set with a mounted filter was filled. Maximum infusion rate was 25 ml/hour. The last empty syringe was replaced with one filled with 20 ml isotonic sodium chloride to infuse the product in set.

    Number of subjects in period 1
    Enrolled subjects
    Started
    13
    Completed
    12
    Not completed
    1
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    All enrolled subjects were included in the Full Analysis Set and the Safety Analysis Set.

    Reporting group values
    Overall trial Total
    Number of subjects
    13 13
    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)
    6 6
        Adolescents (12-17 years)
    3 3
        Adults (18-64 years)
    4 4
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    The age is presented as at treatment baseline (i.e. age of subjects at the first ever dose of velmanase alfa including in earlier trials rhLAMAN-02, rhLAMAN-05 and rhLAMAN-08 ).
    Units: years
        arithmetic mean (standard deviation)
    14.3 ± 9.4 -
    Gender categorical
    Units: Subjects
        Female
    5 5
        Male
    8 8
    Subject analysis sets

    Subject analysis set title
    Paediatric subjects
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Enrolled subjects who were <18 years old at treatment baseline (i.e. when they received the first ever dose of velmanase alfa including in earlier trials rhLAMAN-02, rhLAMAN-05 and rhLAMAN-08).

    Subject analysis set title
    Adult subjects
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Enrolled subjects who were ≥18 years old at treatment baseline (i.e. when they received the first ever dose of velmanase alfa including in earlier trials rhLAMAN-02, rhLAMAN-05 and rhLAMAN-08 ).

    Subject analysis sets values
    Paediatric subjects Adult subjects
    Number of subjects
    9
    4
    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)
    6
    0
        Adolescents (12-17 years)
    3
    0
        Adults (18-64 years)
    0
    4
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    The age is presented as at treatment baseline (i.e. age of subjects at the first ever dose of velmanase alfa including in earlier trials rhLAMAN-02, rhLAMAN-05 and rhLAMAN-08 ).
    Units: years
        arithmetic mean (standard deviation)
    9.4 ± 4.0
    25.3 ± 8.8
    Gender categorical
    Units: Subjects
        Female
    3
    2
        Male
    6
    2

    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 i.v. administration of the investigational medicinal product (IMP) velmanase alfa (recombinant human alpha-mannosidase). All enrolled subjects were included in the Full Analysis Set and the Safety Analysis Set.

    Subject analysis set title
    Paediatric subjects
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Enrolled subjects who were <18 years old at treatment baseline (i.e. when they received the first ever dose of velmanase alfa including in earlier trials rhLAMAN-02, rhLAMAN-05 and rhLAMAN-08).

    Subject analysis set title
    Adult subjects
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Enrolled subjects who were ≥18 years old at treatment baseline (i.e. when they received the first ever dose of velmanase alfa including in earlier trials rhLAMAN-02, rhLAMAN-05 and rhLAMAN-08 ).

    Primary: Number of subjects with infusion-related reactions (IRRs)

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    End point title
    Number of subjects with infusion-related reactions (IRRs) [1]
    End point description
    An adverse drug reaction (ADR) was an AE assessed to be related to study treatment by the Investigator. An IRR was defined as an ADR which occurred during or within 2 hours after the end of the infusion of velmanase alfa and was assessed by the Investigator as being infusion-related. The AEs were classified according to the Medical Dictionary for Regulatory Activities Version 23.0. The IRRs were summarised by System Organ Class and Preferred Term (PT) overall and by age group. The number of subjects experiencing events is presented by PT.
    End point type
    Primary
    End point timeframe
    Data for IRRs were collected from enrolment in rhLAMAN-07 until the end of study.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As per protocol, data have been presented through listings and when applicable summarised, with no inferential statistics implemented.
    End point values
    Enrolled subjects Paediatric subjects Adult subjects
    Number of subjects analysed
    13 [2]
    9 [3]
    4 [4]
    Units: Subject
        Tachycardia
    1
    1
    0
        Diarrhoea
    3
    1
    2
        Vomiting
    2
    2
    0
        Chills
    1
    1
    0
        Fatigue
    1
    1
    0
        Hypokalaemia
    1
    0
    1
        Increased appetite
    1
    0
    1
        Headache
    2
    1
    1
        Cough
    1
    1
    0
        Rash
    1
    1
    0
    Notes
    [2] - Six subjects experienced 22 IRRs.
    [3] - Four paediatric subjects experienced 14 IRRs.
    [4] - Two adult subjects experienced 8 IRRs.
    No statistical analyses for this end point

    Secondary: Absolute change from treatment baseline to time windows for serum oligosaccharides

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    End point title
    Absolute change from treatment baseline to time windows for serum oligosaccharides
    End point description
    Treatment baseline: last non-missing value before first ever dose of velmanase alfa (including in previous trials if subjects enrolled and treated; in rhLAMAN-07 for those not enrolled in earlier trials and placebo group, rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: (date of assessment - date of first ever dose of velmanase alfa)+1) and windowing was performed using the calculated day and a window built around a target day. If >1 time point was reported in the same window, the average of all values was considered in the analysis. Mean (SD) treatment baseline values overall, in paediatric subjects and in adult subjects were 7.925 (3.199), 8.413 (3.902) and 6.950 (0.311) µmol/L, respectively. For 0-12 weeks and time intervals from 156-204, 228-276, 348-372 and 516-612 weeks, data were available for only 1 subject overall. Paired t-test and linear mixed model analyses were performed.
    End point type
    Secondary
    End point timeframe
    Treatment baseline to time windows from start of treatment (0-12 weeks and 24-weekly intervals thereafter until end of study).
    End point values
    Enrolled subjects Paediatric subjects Adult subjects
    Number of subjects analysed
    13
    9 [5]
    4 [6]
    Units: µmol/L
    arithmetic mean (standard deviation)
        12-36 weeks
    -4.480 ± 1.659
    -4.262 ± 1.798
    -5.350 ± 0.495
        36-60 weeks
    -5.240 ± 2.435
    -5.357 ± 2.973
    -4.967 ± 0.153
        60-84 weeks
    -6.063 ± 4.095
    -6.700 ± 4.766
    0 ± 0
        84-108 weeks
    -6.225 ± 4.938
    -6.225 ± 4.938
    0 ± 0
        108-132 weeks
    -4.215 ± 1.827
    -3.725 ± 1.688
    0 ± 0
        204-228 weeks
    -8.988 ± 4.967
    -8.988 ± 4.967
    0 ± 0
        324-348 weeks
    -4.650 ± 0.636
    0 ± 0
    -4.650 ± 0.636
        372-396 weeks
    -5.140 ± 0.924
    -4.750 ± 1.626
    -5.400 ± 0.361
        396-420 weeks
    -4.840 ± 0.503
    -4.900 ± 0.990
    -4.800 ± 0.100
        420-444 weeks
    -5.160 ± 1.309
    -4.900 ± 2.404
    -5.333 ± 0.651
        444-468 weeks
    -4.900 ± 1.017
    -5.250 ± 1.909
    -4.667 ± 0.208
        468-492 weeks
    -5.733 ± 1.097
    -5.550 ± 1.485
    0 ± 0
        492-516 weeks
    -4.975 ± 1.135
    -5.267 ± 1.193
    0 ± 0
    Notes
    [5] - No data for 324-348 weeks.
    [6] - Available data: 1 subject at 60-84, 108-132, 468-492 & 492-516 weeks; none at 84-108 & 204-228 weeks
    No statistical analyses for this end point

    Secondary: Absolute change from treatment baseline to the CEV for CSF oligosaccharides

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    End point title
    Absolute change from treatment baseline to the CEV for CSF oligosaccharides
    End point description
    The mean (SD) treatment baseline values for the overall population, paediatric subjects and adult subjects were 14.200 (7.934), 15.840 (9.889) and 11.467 (2.608) µmol/L, respectively. Of note, treatment baseline values were available for the subjects who performed the CEV and the subject who had enrolled in rhLAMAN-08 who did not perform the CEV.
    End point type
    Secondary
    End point timeframe
    The CEV was performed by subjects who had enrolled in earlier trials rhLAMAN-02 and rhLAMAN-05, a mean of 2.2 years from treatment baseline. Absolute change in CSF oligosaccharide concentration from treatment baseline to the CEV was analysed.
    End point values
    Enrolled subjects Paediatric subjects Adult subjects
    Number of subjects analysed
    7 [7]
    4 [8]
    3 [9]
    Units: µmol/L
        arithmetic mean (standard deviation)
    -1.171 ± 0.720
    -0.875 ± 0.869
    -1.567 ± 0.115
    Notes
    [7] - Seven subjects who had enrolled in rhLAMAN-02 and rhLAMAN-05 performed the CEV.
    [8] - Four paediatric patients who were enrolled in rhLAMAN-02 and rhLAMAN-05 performed the CEV.
    [9] - Three adult subjects who had enrolled in rhLAMAN-02 and rhLAMAN-05 performed the CEV,
    No statistical analyses for this end point

    Secondary: Absolute change from treatment baseline to the CEV for oligosaccharides in 24-hour urine

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    End point title
    Absolute change from treatment baseline to the CEV for oligosaccharides in 24-hour urine
    End point description
    Baseline value was available for 1 paediatric subject (604.000 µmol/L).
    End point type
    Secondary
    End point timeframe
    The CEV was performed by subjects who had enrolled in earlier trials rhLAMAN-02 and rhLAMAN-05, a mean of 2.2 years from treatment baseline. Absolute change in oligosaccharides in 24-hour urine from treatment baseline to the CEV was analysed.
    End point values
    Enrolled subjects Paediatric subjects
    Number of subjects analysed
    1 [10]
    1 [11]
    Units: µmol/L
        number (not applicable)
    -451.900
    -451.900
    Notes
    [10] - Values at treatment baseline and the CEV are available for 1 subject.
    [11] - Values at treatment baseline and the CEV were available for one paediatric subject.
    No statistical analyses for this end point

    Secondary: Absolute change from treatment baseline to time windows for the 6MWT

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    End point title
    Absolute change from treatment baseline to time windows for the 6MWT
    End point description
    Treatment baseline: last non-missing value before first ever dose of velmanase alfa (including in previous trials if subjects enrolled and treated; in rhLAMAN-07 for those not enrolled in earlier trials and placebo group, rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: (date of assessment - date of first ever dose of velmanase alfa)+1); windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between yearly evaluation visits (rhLAMAN-07); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline values for enrolled, paediatric and adult subjects were 472.1 (96.4), 434.5 (74.7) and 547.3 (98.9) metres, respectively. Paired t-test and linear mixed model analyses were performed.
    End point type
    Secondary
    End point timeframe
    Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment. Data available for 1 subject at 12 years.
    End point values
    Enrolled subjects Paediatric subjects Adult subjects
    Number of subjects analysed
    13
    9
    4 [12]
    Units: metre
    arithmetic mean (standard deviation)
        0-6 months
    -17.0 ± 43.8
    -17.0 ± 43.8
    0 ± 0
        1 year
    39.6 ± 48.3
    53.1 ± 54.0
    12.8 ± 17.5
        2 years
    57.0 ± 53.2
    62.7 ± 61.7
    40.0 ± 0.0
        4 years
    16.5 ± 41.5
    21.0 ± 64.5
    12.0 ± 8.9
        6 years
    -3.6 ± 43.9
    31.7 ± 25.7
    -38.8 ± 20.6
        8 years
    -28.4 ± 53.0
    7.5 ± 25.2
    -64.3 ± 50.2
        10 years
    -45.8 ± 103.2
    3.7 ± 36.5
    0 ± 0
    Notes
    [12] - No adults had data available at 0-6 months. Data available for 1 adult at 10 years.
    No statistical analyses for this end point

    Secondary: Absolute change from treatment baseline to time windows for 3MSCT

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    End point title
    Absolute change from treatment baseline to time windows for 3MSCT
    End point description
    Treatment baseline: last non-missing value before first ever dose of velmanase alfa (in previous trials if subjects enrolled and treated; in rhLAMAN-07 for those not enrolled in earlier trials and placebo group, rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: (date of assessment - date of first ever dose of velmanase alfa)+1); windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between yearly evaluation visits (rhLAMAN-07); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline results for enrolled, paediatric and adult subjects were 61.12 (11.06), 59.05 (10.69) and 65.27 (12.14) steps/minute, respectively. Paired t-test and linear mixed model analyses were performed.
    End point type
    Secondary
    End point timeframe
    Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment. Data available for 1 subject at 12 years.
    End point values
    Enrolled subjects Paediatric subjects Adult subjects
    Number of subjects analysed
    13
    9
    4 [13]
    Units: steps/minute
    arithmetic mean (standard deviation)
        0-6 months
    -0.50 ± 10.14
    -0.50 ± 10.14
    0 ± 0
        1 year
    5.48 ± 5.25
    5.53 ± 5.10
    5.39 ± 6.35
        2 years
    5.40 ± 7.39
    6.70 ± 7.40
    1.51 ± 8.25
        4 years
    2.26 ± 5.28
    2.33 ± 6.17
    2.19 ± 5.63
        6 years
    1.83 ± 7.49
    4.74 ± 8.99
    -1.08 ± 5.85
        8 years
    1.92 ± 3.69
    3.78 ± 4.82
    0.07 ± 0.75
        10 years
    -4.16 ± 7.49
    -2.54 ± 8.27
    0 ± 0
    Notes
    [13] - No adults had data available at 0-6 months. Data available for 1 adult at 10 years.
    No statistical analyses for this end point

    Secondary: Absolute change from treatment baseline to time windows for forced vital capacity (FVC) in litres

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    End point title
    Absolute change from treatment baseline to time windows for forced vital capacity (FVC) in litres
    End point description
    Treatment baseline: last non-missing value before first ever dose of velmanase alfa (in previous trials if subjects enrolled and treated; in rhLAMAN-07 for those not enrolled in earlier trials and placebo group, rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: (date of assessment - date of first ever dose of velmanase alfa)+1); windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between yearly evaluation visits (rhLAMAN-07); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline values for enrolled, paediatric and adult subjects were 2.663 (1.185), 2.102 (1.071) and 3.505 (0.852) litres, respectively. Paired t-test and linear mixed model analyses were performed.
    End point type
    Secondary
    End point timeframe
    Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment. At 12 years, data were available for only 1 subject.
    End point values
    Enrolled subjects Paediatric subjects Adult subjects
    Number of subjects analysed
    13
    9
    4 [14]
    Units: litre(s)
    arithmetic mean (standard deviation)
        0-6 months
    0.475 ± 0.431
    0.475 ± 0.431
    0 ± 0
        1 year
    0.508 ± 0.524
    0.650 ± 0.592
    0.295 ± 0.373
        2 years
    0.698 ± 0.802
    0.888 ± 0.794
    0.320 ± 0.948
        4 years
    0.552 ± 0.703
    0.953 ± 0.760
    0.150 ± 0.419
        6 years
    0.550 ± 0.731
    0.940 ± 0.785
    0.160 ± 0.515
        8 years
    0.738 ± 1.213
    1.637 ± 0.993
    -0.160 ± 0.522
        10 years
    1.013 ± 1.218
    1.463 ± 1.003
    0 ± 0
    Notes
    [14] - No adults had data available at 0-6 months. Data available for 1 adult at 10 years.
    No statistical analyses for this end point

    Secondary: Absolute change from treatment baseline to time windows for FVC percent predicted

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    End point title
    Absolute change from treatment baseline to time windows for FVC percent predicted
    End point description
    Treatment baseline: last non-missing value before first ever dose of velmanase alfa (in previous trials if subjects enrolled and treated; in rhLAMAN-07 for those not enrolled in earlier trials and placebo group, rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: (date of assessment - date of first ever dose of velmanase alfa)+1); windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between yearly evaluation visits (rhLAMAN-07); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline values for enrolled, paediatric and adult subjects were were 83.2 (21.9)%, 73.0 (21.0)% and 98.5 (13.4)%, respectively. Paired t-test and linear mixed model analyses were performed.
    End point type
    Secondary
    End point timeframe
    Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment. At 12 years, data were available for only 1 subject.
    End point values
    Enrolled subjects Paediatric subjects Adult subjects
    Number of subjects analysed
    13
    9
    4 [15]
    Units: percentage
    arithmetic mean (standard deviation)
        0-6 months
    11.0 ± 7.1
    11.0 ± 7.1
    0 ± 0
        1 year
    11.7 ± 10.1
    13.5 ± 10.0
    8.9 ± 11.0
        2 years
    15.0 ± 18.0
    16.8 ± 14.8
    11.5 ± 30.4
        4 years
    8.5 ± 13.0
    12.5 ± 12.6
    4.5 ± 14.8
        6 years
    7.8 ± 20.2
    16.8 ± 16.4
    -1.2 ± 22.5
        8 years
    2.1 ± 20.1
    17.0 ± 9.8
    -12.8 ± 15.8
        10 years
    3.4 ± 15.0
    9.8 ± 9.4
    0 ± 0
    Notes
    [15] - No adults had data available at 0-6 months. Data available for 1 adult at 10 years.
    No statistical analyses for this end point

    Secondary: Absolute change from treatment baseline to time windows for forced expiratory volume in the first second (FEV1) (litres)

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    End point title
    Absolute change from treatment baseline to time windows for forced expiratory volume in the first second (FEV1) (litres)
    End point description
    Treatment baseline: last non-missing value before first ever dose of velmanase alfa (in previous trials if subjects enrolled and treated; in rhLAMAN-07 for those not enrolled in earlier trials and placebo group, rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: (date of assessment - date of first ever dose of velmanase alfa)+1); windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between yearly evaluation visits (rhLAMAN-07); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Averages of values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline values for enrolled, paediatric and adult subjects were 2.372 (1.050), 1.928 (0.969) and 3.038 (0.871) litres, respectively. Paired t-test and linear mixed model analyses were performed.
    End point type
    Secondary
    End point timeframe
    Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment. At 12 years, data were available for only 1 subject.
    End point values
    Enrolled subjects Paediatric subjects Adult subjects
    Number of subjects analysed
    13
    9
    4 [16]
    Units: litre(s)
    arithmetic mean (standard deviation)
        0-6 months
    0.425 ± 0.233
    0.425 ± 0.233
    0 ± 0
        1 year
    0.438 ± 0.507
    0.602 ± 0.549
    0.193 ± 0.367
        2 years
    0.568 ± 0.690
    0.728 ± 0.590
    0.250 ± 1.018
        4 years
    0.380 ± 0.516
    0.735 ± 0.658
    0.143 ± 0.327
        6 years
    0.493 ± 0.663
    0.777 ± 0.825
    0.210 ± 0.422
        8 years
    0.568 ± 1.062
    1.260 ± 1.051
    -0.123 ± 0.531
        10 years
    0.663 ± 1.043
    0.983 ± 1.007
    0 ± 0
    Notes
    [16] - No adults had data available at 0-6 months. Data available for 1 adult at 10 years.
    No statistical analyses for this end point

    Secondary: Absolute change from treatment baseline to time windows for FEV1 percent predicted

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    End point title
    Absolute change from treatment baseline to time windows for FEV1 percent predicted
    End point description
    Treatment baseline: last non-missing value before first ever dose of velmanase alfa (in previous trials if subjects enrolled and treated; in rhLAMAN-07 for those not enrolled in earlier trials and placebo group, rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: (date of assessment - date of first ever dose of velmanase alfa)+1); windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between yearly evaluation visits (rhLAMAN-07); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline values for enrolled, paediatric and adult subjects were 82.0 (19.3)%, 74.8 (18.0)% and 92.8 (18.0)%, respectively. Paired t-test and linear mixed model analyses were performed.
    End point type
    Secondary
    End point timeframe
    Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment. At 12 years, data were available for only 1 subject.
    End point values
    Enrolled subjects Paediatric subjects Adult subjects
    Number of subjects analysed
    13
    9
    4 [17]
    Units: percentage
    arithmetic mean (standard deviation)
        0-6 months
    11.0 ± 2.8
    11.0 ± 2.8
    0 ± 0
        1 year
    11.4 ± 12.2
    14.7 ± 12.5
    6.4 ± 11.7
        2 years
    12.6 ± 18.2
    14.1 ± 11.8
    9.5 ± 34.6
        4 years
    7.1 ± 9.1
    10.8 ± 3.9
    4.7 ± 11.6
        6 years
    8.3 ± 16.4
    12.8 ± 17.3
    3.7 ± 17.7
        8 years
    5.6 ± 19.5
    15.2 ± 20.3
    -4.1 ± 16.2
        10 years
    3.4 ± 16.9
    7.8 ± 17.6
    0 ± 0
    Notes
    [17] - No adults had data available at 0-6 months. Data available for 1 adult at 10 years.
    No statistical analyses for this end point

    Secondary: Absolute change from treatment baseline to time windows for peak expiratory flow (PEF)

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    End point title
    Absolute change from treatment baseline to time windows for peak expiratory flow (PEF)
    End point description
    Treatment baseline: last non-missing value before first ever dose of velmanase alfa (in previous trials if subjects enrolled and treated; in rhLAMAN-07 for those not enrolled in earlier trials and placebo group, rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: (date of assessment - date of first ever dose of velmanase alfa)+1); windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between yearly evaluation visits (rhLAMAN-07); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if there was >1 time point in the same window for a subject. Mean (SD) treatment baseline results for enrolled, paediatric and adult subjects were 4.918 (2.390), 3.967 (1.841) and 6.345 (2.638) litres per second, respectively. Paired t-test and linear mixed model analyses were done.
    End point type
    Secondary
    End point timeframe
    Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment. Data were only available for 1 subject at 12 years.
    End point values
    Enrolled subjects Paediatric subjects Adult subjects
    Number of subjects analysed
    13
    9
    4 [18]
    Units: litres per second
    arithmetic mean (standard deviation)
        0-6 months
    1.335 ± 0.346
    1.335 ± 0.346
    0 ± 0
        1 year
    1.136 ± 1.345
    0.895 ± 0.741
    1.497 ± 2.055
        2 years
    1.178 ± 2.178
    1.320 ± 1.010
    0.895 ± 4.518
        4 years
    1.083 ± 0.813
    1.223 ± 0.883
    0.943 ± 0.903
        6 years
    1.168 ± 1.367
    1.237 ± 1.546
    1.100 ± 1.507
        8 years
    0.785 ± 2.587
    2.550 ± 1.886
    -0.980 ± 1.957
        10 years
    1.278 ± 2.073
    1.787 ± 2.211
    0 ± 0
    Notes
    [18] - No adults had data available at 0-6 months. Data available for 1 adult at 10 years.
    No statistical analyses for this end point

    Secondary: Absolute change from treatment baseline to time windows for CHAQ Disability Index

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    End point title
    Absolute change from treatment baseline to time windows for CHAQ Disability Index
    End point description
    Treatment baseline: last non-missing value before first ever dose of velmanase alfa (in previous trials if subjects enrolled and treated; in rhLAMAN-07 for those not enrolled in earlier trials and placebo group, rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: (date of assessment - date of first ever dose of velmanase alfa)+1); windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between yearly evaluation visits (rhLAMAN-07); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline scores for enrolled, paediatric and adult subjects were 1.365 (0.743), 1.484 (0.836) and 1.125 (0.530), respectively. The CHAQ-DI can range from 0 to 3; higher score indicates worsening.
    End point type
    Secondary
    End point timeframe
    Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment. At 12 years, data were available for only 1 subject.
    End point values
    Enrolled subjects Paediatric subjects Adult subjects
    Number of subjects analysed
    13
    9
    4 [19]
    Units: score
    arithmetic mean (standard deviation)
        0-6 months
    0.313 ± 0.795
    0.313 ± 0.795
    0 ± 0
        1 year
    -0.078 ± 0.398
    -0.086 ± 0.459
    -0.063 ± 0.298
        2 years
    -0.125 ± 0.634
    -0.125 ± 0.680
    -0.125 ± 0.707
        4 years
    0.156 ± 0.462
    0.083 ± 0.674
    0.229 ± 0.253
        6 years
    -0.094 ± 0.675
    -0.271 ± 0.989
    0.083 ± 0.260
        8 years
    0.240 ± 0.325
    0.139 ± 0.446
    0.340 ± 0.187
        10 years
    0.688 ± 0.971
    0.458 ± 1.048
    0 ± 0
    Notes
    [19] - No adults had data available at 0-6 months. Data available for 1 adult at 10 years.
    No statistical analyses for this end point

    Secondary: Absolute change from treatment baseline to time windows for CHAQ Visual Analogue Scale (VAS) Pain

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    End point title
    Absolute change from treatment baseline to time windows for CHAQ Visual Analogue Scale (VAS) Pain
    End point description
    Treatment baseline: last non-missing value before first ever dose of velmanase alfa (in previous trials if subjects enrolled and treated; in rhLAMAN-07 for those not enrolled in earlier trials and placebo group, rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: (date of assessment - date of first ever dose of velmanase alfa)+1); windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between yearly evaluation visits (rhLAMAN-07); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline results for enrolled, paediatric and adult subjects were 0.583 (0.698), 0.799 (0.764) and 0.150 (0.227), respectively. Scores range from 0 (no pain) to 3 (very severe pain).
    End point type
    Secondary
    End point timeframe
    Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment. At 12 years, data were only available for 1 subject.
    End point values
    Enrolled subjects Paediatric subjects Adult subjects
    Number of subjects analysed
    13
    9
    4 [20]
    Units: score
    arithmetic mean (standard deviation)
        0-6 months
    0.330 ± 0.297
    0.330 ± 0.297
    0 ± 0
        1 year
    -0.041 ± 1.032
    -0.259 ± 1.183
    0.394 ± 0.508
        2 years
    -0.195 ± 0.398
    -0.230 ± 0.393
    -0.090 ± 0.552
        4 years
    -0.013 ± 0.344
    -0.145 ± 0.403
    0.120 ± 0.286
        6 years
    -0.020 ± 0.381
    -0.150 ± 0.556
    0.110 ± 0.062
        8 years
    0.293 ± 0.597
    0.047 ± 0.631
    0.538 ± 0.558
        10 years
    0.548 ± 0.908
    0.190 ± 0.686
    0 ± 0
    Notes
    [20] - No adults had data available at 0-6 months. Data available for 1 adult at 10 years.
    No statistical analyses for this end point

    Secondary: Absolute change from treatment baseline to time windows for CHAQ VAS General

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    End point title
    Absolute change from treatment baseline to time windows for CHAQ VAS General
    End point description
    Treatment baseline: last non-missing value before first ever dose of velmanase alfa (in previous trials if subjects enrolled and treated; in rhLAMAN-07 for those not enrolled in earlier trials and placebo group, rhLAMAN-05). Assessments during treatment were assigned to a time point (calculation: (date of assessment - date of first ever dose of velmanase alfa)+1); windowing was performed using the calculated day and a window built around a target day. Six months (183 days) to 365 days were accepted between yearly evaluation visits (rhLAMAN-07); dates >365 days+183 days after a visit belonged to the next visit and dates <183 days from a visit belonged to that visit. Average values were used for analysis if >1 time point was reported in the same window for a subject. Mean (SD) treatment baseline scores for enrolled, paediatric and adult subjects were 1.365 (0.797), 1.286 (0.914) and 1.523 (0.573), respectively. Scores range from 0 to 3; higher scores indicate lower quality of life.
    End point type
    Secondary
    End point timeframe
    Treatment baseline to 0-6, 6-18, 18-36, 36-60, 60-84, 84-108, 108-132 and 132-156 months (i.e. post-treatment baseline and 1, 2, 4, 6, 8, 10 and 12 years, respectively) from start of treatment. At 12 years, data were available for only 1 subject.
    End point values
    Enrolled subjects Paediatric subjects Adult subjects
    Number of subjects analysed
    13
    9
    4 [21]
    Units: score
    arithmetic mean (standard deviation)
        0-6 months
    0.030 ± 0.636
    0.030 ± 0.636
    0 ± 0
        1 year
    -0.211 ± 1.286
    -0.242 ± 1.569
    -0.150 ± 0.559
        2 years
    0.008 ± 1.012
    -0.195 ± 1.094
    0.615 ± 0.445
        4 years
    0.485 ± 0.561
    0.750 ± 0.455
    0.220 ± 0.608
        6 years
    -0.318 ± 1.107
    -0.410 ± 1.115
    -0.225 ± 1.339
        8 years
    0.454 ± 0.816
    0.863 ± 1.065
    0.045 ± 0.169
        10 years
    0.649 ± 0.381
    0.465 ± 0.123
    0 ± 0
    Notes
    [21] - No adults had data available at 0-6 months. Data available for 1 subject at 10 years.
    No statistical analyses for this end point

    Other pre-specified: Detection of ADAs

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    End point title
    Detection of ADAs
    End point description
    Detection of ADAs was a secondary objective and safety endpoint. Blood samples were collected for ADA assessments prior to first dose of velmanase alfa for subjects not previously enrolled in a velmanase alfa trial, every 12 weeks during rhLAMAN-07 for all patients and during the CEV for patients who had enrolled in rhLAMAN-02 and rhLAMAN-05 (who performed the visit). For subjects who had received placebo during rhLAMAN-05, the first ADA assessment was considered as treatment baseline but only if captured not more than 7 days after the first study treatment administration. Subjects were considered to be ADA-positive if they were positive at treatment baseline or had an ADA-positive test at least once during rhLAMAN-07. Subjects were considered to be ADA-negative if they had no ADA-positive tests. At treatment baseline, 10 subjects were ADA-negative and 3 subjects were ADA-positive. The number of subjects who were ADA-positive/negative as defined above, is presented.
    End point type
    Other pre-specified
    End point timeframe
    At treatment baseline (i.e. prior to first ever dose of velmanase alfa including in previous trials) and during rhLAMAN-07.
    End point values
    Enrolled subjects
    Number of subjects analysed
    13
    Units: Subject
        Positive
    11
        Negative
    2
    No statistical analyses for this end point

    Other pre-specified: Absolute change from treatment baseline to time windows for serum IgG

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    End point title
    Absolute change from treatment baseline to time windows for serum IgG
    End point description
    Serum IgG was a safety laboratory parameter which can also be considered a pharmacodynamic marker. Treatment baseline values were only available for 4 subjects who were not previously enrolled in a velmanase alfa trial. The assessments during the trial were allocated to 6-month intervals based on the duration since the first dose of velmanase alfa in rhLAMAN-07. If there was >1 assessment per interval for the same subject, the average was used in the analysis. Mean (SD) treatment baseline value overall was 5.983 (1.414) grams/litre. Paired t-test analysis was performed.
    End point type
    Other pre-specified
    End point timeframe
    Trial (also treatment) baseline to 6-monthly intervals until the end of trial (i.e. 0-6, 6-12, 12-18, 18-24 and 24-30 months).
    End point values
    Enrolled subjects
    Number of subjects analysed
    4 [22]
    Units: gram(s)/litre
    arithmetic mean (standard deviation)
        0-6 months
    2.610 ± 0.833
        6-12 months
    2.779 ± 0.491
        12-18 months
    3.157 ± 0.539
        18-24 months
    3.360 ± 0.000
        24-30 months
    4.370 ± 0.042
    Notes
    [22] - Four subjects not previously enrolled in a velmanase alfa trial with treatment baseline values.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) were collected from the time of informed consent in rhLAMAN-07, for the duration of the trial.
    Adverse event reporting additional description
    All TEAEs were collected from spontaneous, unsolicited reports of subjects, by observation and by routine open questioning.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Enrolled subjects
    Reporting group description
    This was an open-label trial where all enrolled subjects received once weekly i.v. administration of the investigational medicinal product (IMP) velmanase alfa (recombinant human alpha-mannosidase). All enrolled subjects were included in the full analysis set and the safety analysis set.

    Reporting group title
    Paediatric subjects
    Reporting group description
    Subjects aged <18 years at the time of first ever dose of velmanase alfa

    Reporting group title
    Adult subjects
    Reporting group description
    Subjects aged ≥18 years at the time of first ever dose of velmanase alfa.

    Serious adverse events
    Enrolled subjects Paediatric subjects Adult subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 13 (46.15%)
    4 / 9 (44.44%)
    2 / 4 (50.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Enrolled subjects Paediatric subjects Adult subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 13 (100.00%)
    9 / 9 (100.00%)
    4 / 4 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 9 (22.22%)
    0 / 4 (0.00%)
         occurrences all number
    3
    3
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Hypertension
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Poor venous access
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 9 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    4
    0
    4
    Surgical and medical procedures
    Catheter placement
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    2
    Wisdom teeth removal
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    General disorders and administration site conditions
    Axillary pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    2
    Catheter site erythema
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    2
    Catheter site oedema
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Chills
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    7
    7
    0
    Complication associated with device
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Crying
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Extravasation
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 13 (23.08%)
    2 / 9 (22.22%)
    1 / 4 (25.00%)
         occurrences all number
    5
    3
    2
    Hyperthermia
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    4
    3
    1
    Malaise
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 9 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    4
    0
    4
    Oedema peripheral
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    3
    3
    0
    Pyrexia
         subjects affected / exposed
    6 / 13 (46.15%)
    5 / 9 (55.56%)
    1 / 4 (25.00%)
         occurrences all number
    12
    8
    4
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Testicular pain
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    2
    2
    0
    COVID-19
         subjects affected / exposed
    4 / 13 (30.77%)
    3 / 9 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    4
    3
    1
    Cough
         subjects affected / exposed
    6 / 13 (46.15%)
    4 / 9 (44.44%)
    2 / 4 (50.00%)
         occurrences all number
    16
    13
    3
    Oropharyngeal pain
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    1
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Anxiety
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Behaviour disorder
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    2
    Encopresis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Enuresis
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    1
    Hallucination
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    4
    0
    4
    Sleep disorder
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    1
    Somnambulism
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Investigations
    Aspiration bone marrow
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Injury, poisoning and procedural complications
    Epicondylitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Fall
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Hand fracture
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Product administration error
         subjects affected / exposed
    3 / 13 (23.08%)
    2 / 9 (22.22%)
    1 / 4 (25.00%)
         occurrences all number
    8
    7
    1
    Road traffic accident
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Scar
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Scratch
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Skin wound
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Traumatic arthrosis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Traumatic haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Upper limb fracture
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Wound
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Congenital, familial and genetic disorders
    Familial mediterranean fever
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Hereditary retinal dystrophy
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Bradycardia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Tachycardia
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Cervical radiculopathy
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Headache
         subjects affected / exposed
    5 / 13 (38.46%)
    2 / 9 (22.22%)
    3 / 4 (75.00%)
         occurrences all number
    8
    2
    6
    Paraesthesia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Seizure
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Somnolence
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Speech disorder
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    4
    4
    0
    Otorrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Vertigo
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Lacrimation increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Abdominal pain
         subjects affected / exposed
    7 / 13 (53.85%)
    4 / 9 (44.44%)
    3 / 4 (75.00%)
         occurrences all number
    12
    8
    4
    Abdominal pain lower
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Anal incontinence
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Constipation
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    4
    1
    3
    Defaecation urgency
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Dental caries
         subjects affected / exposed
    3 / 13 (23.08%)
    3 / 9 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    3
    3
    0
    Diarrhoea
         subjects affected / exposed
    5 / 13 (38.46%)
    3 / 9 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    13
    5
    8
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Haemorrhoids
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    1
    Inguinal hernia
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Nausea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    0
    3
    Toothache
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Vomiting
         subjects affected / exposed
    7 / 13 (53.85%)
    6 / 9 (66.67%)
    1 / 4 (25.00%)
         occurrences all number
    11
    8
    3
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    2
    Hyperkeratosis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Intertrigo
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Purpura
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Rash
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    1
    Scar pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Skin lesion
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Urinary incontinence
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 13 (30.77%)
    2 / 9 (22.22%)
    2 / 4 (50.00%)
         occurrences all number
    10
    4
    6
    Arthritis
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    3
    2
    1
    Back pain
         subjects affected / exposed
    4 / 13 (30.77%)
    2 / 9 (22.22%)
    2 / 4 (50.00%)
         occurrences all number
    6
    2
    4
    Bone pain
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Foot deformity
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Kyphosis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Neck pain
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 9 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    2
    0
    2
    Pain in extremity
         subjects affected / exposed
    4 / 13 (30.77%)
    2 / 9 (22.22%)
    2 / 4 (50.00%)
         occurrences all number
    11
    7
    4
    Pseudarthrosis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    2
    2
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 9 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    2
    0
    2
    COVID-19
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    2
    2
    0
    Cystitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Device related infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Ear infection
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    1
    Fungal infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Furuncle
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Influenza
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    6 / 13 (46.15%)
    4 / 9 (44.44%)
    2 / 4 (50.00%)
         occurrences all number
    12
    8
    4
    Oral herpes
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    2
    Otitis media
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Rhinitis
         subjects affected / exposed
    5 / 13 (38.46%)
    4 / 9 (44.44%)
    1 / 4 (25.00%)
         occurrences all number
    9
    7
    2
    Tonsillitis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Tracheitis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 9 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    1
    Metabolism and nutrition disorders
    Calcium deficiency
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Increased appetite
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Iron deficiency
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Overweight
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Vitamin B12 deficiency
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 9 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jan 2015
    In Amendment number 1 to Protocol Version 2.0 dated 07 July 2013, Poland was included as a centre and the number of sites was increased to 12 (in France and Poland) with an increase in the number of subjects who could be enrolled to 12. Dose visits could be performed in hospitals in both countries and only for subjects in France at Lyon. In Amendment number 2 to Protocol Version 2.0 dated 07 April 2013, The trial objective was updated to include evaluation of efficacy of repeated i.v. administration of velmanase alfa and a CEV was added to evaluate additional efficacy parameters. The secondary efficacy objectives added were: evaluation of impact of long-term treatment with velmanase alfa upon serum oligosaccharides, endurance (as measured by the 3MSCT and 6MWT), pulmonary function, motor proficiency (Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition), hearing, cognitive development (Leiter International Performance Scale - Revised), central nervous system involvement (only in subjects who had participated in rhLAMAN-02 and had baseline assessments for the imaging studies), biomarkers and oligosaccharides in CSF and oligosaccharide clearance in urine (only at the CEV) and quality of life (questionnaires). Assessment of in vivo biological activity in plasma and pharmacokinetic analysis were added to secondary objectives. A safety objective of monitoring immunogenicity (ADAs) throughout the trial was added. Additional safety assessments were added at the CEV including haematology, coagulation tests, biochemistry, anti-nuclear antibodies, urinalysis, serum IgG/IgA/IgM, 12-lead electrocardiogram and echocardiogram. Assessment of changes in social and leisure skills was also planned during the CEV. Interim analysis of data from the CEV was planned. A new protocol version was not produced after these amendments and both were submitted together and approved.
    17 May 2016
    In Amendment number 3 dated 11 March 2016 to Protocol Version 2.0 dated 07 June 2013, the duration of the study was prolonged to 6 years. Implantation of an i.v. catheter to ease delivery of velmanase alfa and other i.v. procedures was permitted at the Investigator's discretion. Assessment of pulmonary function and collection of concomitant medication/therapy at yearly evaluation visits was added to the trial flow chart. The Protocol Version 3.0 dated 31 March 2016 and updated table of changes between Protocol Amendments 2 and 3 to Protocol Version 2.0 were submitted to the Regulatory Authority and approved.
    28 Dec 2016
    Protocol Version 4.0 dated 09 November 2016 reflected change in Sponsor from Zymenex to Chiesi and name of study treatment was changed from Lamazyn to velmanase alfa.
    10 Dec 2019
    The main changes from Protocol Versions 4.0 to 6.0 (of note, Version 5.0 was not distributed and superseded by Version 6.0) included increase in number to subjects who could be enrolled to 13 including 7 who had been enrolled in rhLAMAN-02 and rhLAMAN-05, 1 who had been enrolled in rhLAMAN-08 and 5 who had not previously been enrolled in a velmanase alfa trial, with consequent update in title and inclusion criteria; extension of trial duration to third quarter of 2022; planned evaluation of serum oligosaccharides and Ig (for safety) every 24 weeks; planned collection of baseline data for efficacy assessments and safety assessments at Visit 1 and yearly evaluations in Lyon, France for subjects not previously enrolled in a velmanase alfa trial and the subject from rhLAMAN-08 (as applicable).
    02 Jun 2020
    This was Substantial General Amendment number 1 to Protocol Version 6.0 dated 18 October 2019. It was specified that the trial was extended up to the third quarter of 2022 to support collection of long-term efficacy and safety data of velmanase alfa and allow further collection of data in an interventional trial setting during a prolonged observation period considering the slow progression of alpha-mannosidosis and to leverage the fact that this allows increased knowledge of an ultra-rare pathology in a specific and well-studied cohort of subjects.
    21 Jul 2020
    This was Substantial General Amendment number 2 to Protocol Version 6.0 dated 18 October 2019. The home infusion setting was implemented for eligible subjects. Applicable sections of the protocol were updated as a result and a new section (Section 8.4.6) was inserted specifying details of the programme. The operating manual (Version 1.0 dated 16 June 2020) was also developed. With subject consent, data collected in the electronic Case Report Form during the trial was permitted to be transferred to the French retrospective Registry (Etoile alpha). A new section in the protocol included details of the Registry.
    26 Nov 2020
    This was Substantial General Amendment number 3 to the Protocol Version 6.0 dated 18 October 2019 (as amended by Substantial General Amendments numbers 1 and 2). Additional blood samples were to be collected to further investigate the immunological response of subjects, with testing of the vaccination response to poliovirus, diphtheria toxin, tetanus toxin, Pneumococcal polysaccharide and Haemophilus influenzae type b. It was specified that remnants of samples already analysed for the trial could be used for external research purposes. Changes to trial database and Contract Research Organisations were specified and typographical errors were corrected. Sections of the protocol were updated to reflect the changes, an additional safety endpoint of immunological response to vaccines was added, the study flow chart was updated and a new section was added to the protocol including details about additional sample collection for immunological response to vaccines. It was specified that the yearly evaluation visits would be shifted from the Copenhagen University Hospital in Denmark to the Hôpital Femme Mère Enfant in Lyon, France to avoid foreign travel for subjects/relatives during the COVID-19 pandemic and ensure that the visits would be performed. It was also specified that the interval between successive yearly visits could not be more than 7 months. The laboratories for ADA, neutralising antibody and oligosaccharide testing were specified.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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