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    Clinical Trial Results:
    A multi-center, open-label trial of the long-term efficacy and safety of Lamazym for the treatment of patients with alpha-Mannosidosis.

    Summary
    EudraCT number
    		 2011-004355-40
    Trial protocol
    		 DK   DE   BE   GB   ES  
    Global end of trial date
    20 Sep 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Aug 2016
    First version publication date
    11 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    rhLAMAN-04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01681940
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Zymenex A/S
    Sponsor organisation address
    Roskildevej 12C, Hilleroed, Denmark, 3400
    Public contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., clinicalTrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., clinicalTrials_info@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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Sep 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall objective of this trial is the evaluation of long-term efficacy, safety and tolerability of Lamazym treatment in patients with alpha-Mannosidosis. The primary objectives of the trial are: Evaluation of long-term efficacy from baseline of Lamazym on reduction of the biomarker Oligosaccharides in blood and CSF and an improvement in the 3 minute stair climb, 6 minute walk test and pulmonary function from baseline.
    Protection of trial subjects
    The study was conducted in accordance with the declaration of Helsinki, good clinical practice (GCP) guidelines and local law requirements. Other than routine care, no specific measures for protection of trial subjects were implemented.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Jan 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    10
    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)
    5
    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
    		 A total of 10 patients were enrolled in the rhLAMAN-02 and rhLAMAN-03 trials. One (1) patient (Patient 03) was withdrawn from treatment in the rhLAMAN-03 trial after approximately 2.5 months of treatment and was subsequently withdrawn from the trial. All 9 patients who completed the rhLAMAN-03 trial continued into the rhLAMAN-04 trial.

    Pre-assignment
    Screening details
    		 No patients failed screening or withdrew from the rhLAMAN-04 trial

    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
    		 Lamazym
    Arm description
    		 In the Laman04 study, all patients were treated with the same dose: 1 mg/kg body weight, and each patient received weekly i.v. infusions of Lamazym with 7 days ± 2 days required between each infusion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lamazym
    Investigational medicinal product code
    Other name
    recombinant human alpha-mannosidase
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the Laman04 all patients were treated with the same dose: 1 mg/kg body weight, and each patient received weekly i.v. infusions of Lamazym with 7 days ± 2 days required between each infusion

    Number of subjects in period 1
    		Lamazym
    Started
    10
    Completed
    9
    Not completed
    1
         Adverse event, non-fatal
    1

    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
    		 10 10
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.8 ± 3.7 -
    Gender categorical
    Units: Subjects
        Female
    		 3 3
        Male
    		 7 7
    Subject analysis sets

    Subject analysis set title
    Baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) includes all 10 patients receiving the investigational medicinal product in at least one of the rhLAMAN-02, rhLAMAN-03 and rhLAMAN-04. The FAS corresponds to the efficacy analysis set.

    Subject analysis set title
    End evaluation
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    End evaluation is made at Visit 26a of the rhLAMAN04 study

    Subject analysis sets values
    		 Baseline End evaluation
    Number of subjects
    10
    9
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    11.8 ± 3.7
    11.8 ± 3.7
    Gender categorical
    Units: Subjects
        Female
    3
    2
        Male
    7
    7

    End points

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    End points reporting groups
    Reporting group title
    Lamazym
    Reporting group description
    		 In the Laman04 study, all patients were treated with the same dose: 1 mg/kg body weight, and each patient received weekly i.v. infusions of Lamazym with 7 days ± 2 days required between each infusion

    Subject analysis set title
    Baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) includes all 10 patients receiving the investigational medicinal product in at least one of the rhLAMAN-02, rhLAMAN-03 and rhLAMAN-04. The FAS corresponds to the efficacy analysis set.

    Subject analysis set title
    End evaluation
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    End evaluation is made at Visit 26a of the rhLAMAN04 study

    Primary: Change from baseline in blood serum oligosaccharides

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    End point title
    		 Change from baseline in blood serum oligosaccharides
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.1 of the CSR
    End point type
    Primary
    End point timeframe
    Serum oligosaccharides were measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: umol/L
        arithmetic mean (standard deviation)
    9.4 ± 2.88
    -8.11 ± 3.1
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval

    Primary: Change from baseline in CSF oligosaccharides

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    End point title
    		 Change from baseline in CSF oligosaccharides
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.3 of the CSR
    End point type
    Primary
    End point timeframe
    CSF oligosaccharides were measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: umol/L
        arithmetic mean (standard deviation)
    10.7 ± 4.55
    -1.67 ± 2.55
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.086
    Method
    		 ANCOVA
    Confidence interval

    Primary: Change from baseline in 3-min stair climb

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    End point title
    		 Change from baseline in 3-min stair climb
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.4 of the CSR
    End point type
    Primary
    End point timeframe
    Stair climbing was assessed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: steps
        arithmetic mean (standard deviation)
    156.7 ± 40.48
    39.33 ± 29.59
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.004
    Method
    		 ANCOVA
    Confidence interval

    Primary: Change from baseline in 6-min walk test

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    End point title
    		 Change from baseline in 6-min walk test
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.5 of the CSR
    End point type
    Primary
    End point timeframe
    6-minute walk test was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: min
        arithmetic mean (standard deviation)
    444.45 ± 104.03
    71.17 ± 62.8
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.009
    Method
    		 ANCOVA
    Confidence interval

    Primary: Change from baseline in pulmonary FVC

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    End point title
    		 Change from baseline in pulmonary FVC
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.6 of the CSR
    End point type
    Primary
    End point timeframe
    FVC was measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: liters
        arithmetic mean (standard deviation)
    2.07 ± 0.91
    0.6 ± 0.44
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.003
    Method
    		 ANCOVA
    Confidence interval

    Primary: Change from baseline of pulmonary FVC as percent of predicted normal value

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    End point title
    		 Change from baseline of pulmonary FVC as percent of predicted normal value
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.7 of the CSR
    End point type
    Primary
    End point timeframe
    FVC was measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 12), and at rhLAMAN-04 evaluation (Visit 26a, month 18).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: percent
        arithmetic mean (standard deviation)
    79.05 ± 15.78
    9.17 ± 17.63
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.157
    Method
    		 ANCOVA
    Confidence interval

    Primary: Change from baseline in pulmonary FEV1

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    End point title
    		 Change from baseline in pulmonary FEV1
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.8 of the CSR
    End point type
    Primary
    End point timeframe
    FEV1 was measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 12), and at rhLAMAN-04 evaluation (Visit 26a, month 18).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: Liters
        arithmetic mean (standard deviation)
    1.93 ± 0.85
    0.28 ± 0.33
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    End evaluation v Baseline
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.035
    Method
    		 ANCOVA
    Confidence interval

    Primary: Change from baseline in pulmonary FEV1 as percent of predicted normal value

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    End point title
    		 Change from baseline in pulmonary FEV1 as percent of predicted normal value
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.9 of the CSR
    End point type
    Primary
    End point timeframe
    FEV1 was measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: percent
        arithmetic mean (standard deviation)
    79.1 ± 15.62
    -0.11 ± 16.86
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    End evaluation v Baseline
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.985
    Method
    		 ANCOVA
    Confidence interval

    Primary: Change from baseline in pulmonary peak expiratory flow rate

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    End point title
    		 Change from baseline in pulmonary peak expiratory flow rate
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.10 of the CSR
    End point type
    Primary
    End point timeframe
    PEF rate was measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: L/sec
        arithmetic mean (standard deviation)
    3.71 ± 1.52
    0.4 ± 0.92
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.23
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in BOT2 balance

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    End point title
    		 Change from baseline in BOT2 balance
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.11 of the CSR
    End point type
    Secondary
    End point timeframe
    BOT2 was measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 12), and at rhLAMAN-04 evaluation (Visit 26a, month 18).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: integer
        arithmetic mean (standard deviation)
    14.7 ± 7.13
    0.11 ± 4.78
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    End evaluation v Baseline
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.946
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in BOT2 bilateral coordination

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    End point title
    		 Change from baseline in BOT2 bilateral coordination
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.12 of the CSR
    End point type
    Secondary
    End point timeframe
    BOT2 was measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 12), and at rhLAMAN-04 evaluation (Visit 26a, month 18).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: integer
        arithmetic mean (standard deviation)
    11.4 ± 5.1
    3.11 ± 2.57
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.007
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in BOT2 running speed and agility

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    End point title
    		 Change from baseline in BOT2 running speed and agility
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.13 of the CSR
    End point type
    Secondary
    End point timeframe
    BOT2 was measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: integer
        arithmetic mean (standard deviation)
    13.7 ± 7.2
    2.11 ± 2.71
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.048
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in BOT2 upper limb coordination

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    End point title
    		 Change from baseline in BOT2 upper limb coordination
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.14 of the CSR
    End point type
    Secondary
    End point timeframe
    BOT2 was measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: integer
        arithmetic mean (standard deviation)
    16.7 ± 12.6
    3.33 ± 8.14
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.254
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in BOT2 manual dexterity

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    End point title
    		 Change from baseline in BOT2 manual dexterity
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.15 of the CSR
    End point type
    Secondary
    End point timeframe
    BOT2 was measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 12), and at rhLAMAN-04 evaluation (Visit 26a, month 18).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: integer
        arithmetic mean (standard deviation)
    14.9 ± 6.31
    1.89 ± 2.52
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    End evaluation v Baseline
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.055
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in BOT2 fine motor integration

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    End point title
    		 Change from baseline in BOT2 fine motor integration
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.16 of the CSR
    End point type
    Secondary
    End point timeframe
    BOT2 was measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: integer
        arithmetic mean (standard deviation)
    19.8 ± 12.04
    0.67 ± 5.74
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.737
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in BOT2 fine motor precision

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    End point title
    		 Change from baseline in BOT2 fine motor precision
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.17 of the CSR
    End point type
    Secondary
    End point timeframe
    BOT2 was measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 12), and at rhLAMAN-04 evaluation (Visit 26a, month 18).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: integer
        arithmetic mean (standard deviation)
    23.4 ± 9.79
    3.67 ± 3.2
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.009
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in CSF-GFAp

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    End point title
    		 Change from baseline in CSF-GFAp
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.18 of the CSR
    End point type
    Secondary
    End point timeframe
    CSF biomarkers were measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: ng/L
        arithmetic mean (standard deviation)
    807 ± 334.5
    -364.44 ± 199.07
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    End evaluation v Baseline
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in CSF-NFLp

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    End point title
    		 Change from baseline in CSF-NFLp
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.19 of the CSR
    End point type
    Secondary
    End point timeframe
    CSF biomarkers were measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: ng/L
        arithmetic mean (standard deviation)
    606 ± 228.68
    -180 ± 176.64
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.016
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in CSF-Tau

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    End point title
    		 Change from baseline in CSF-Tau
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.20 of the CSR
    End point type
    Secondary
    End point timeframe
    CSF biomarkers were measured at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: ng/L
        arithmetic mean (standard deviation)
    711 ± 305.34
    -58.44 ± 112.96
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    End evaluation v Baseline
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.159
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in Leiter R test score - Design analogies

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    End point title
    		 Change from baseline in Leiter R test score - Design analogies
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.26 of the CSR
    End point type
    Secondary
    End point timeframe
    Leiter R test was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: integer
        arithmetic mean (standard deviation)
    5.86 ± 1.61
    0.75 ± 1.36
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.137
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in Leiter R test score - Figure ground

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    End point title
    		 Change from baseline in Leiter R test score - Figure ground
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.27 of the CSR
    End point type
    Secondary
    End point timeframe
    Leiter R test was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: integer
        arithmetic mean (standard deviation)
    6.59 ± 1.18
    0.27 ± 0.85
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    End evaluation v Baseline
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.372
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in Leiter R test score - Form completion

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    End point title
    		 Change from baseline in Leiter R test score - Form completion
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.28 of the CSR
    End point type
    Secondary
    End point timeframe
    Leiter R test was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: Integer
        arithmetic mean (standard deviation)
    6.11 ± 1.43
    0.87 ± 0.92
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.022
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in Leiter R test score - Paper folding

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    End point title
    		 Change from baseline in Leiter R test score - Paper folding
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.29 of the CSR
    End point type
    Secondary
    End point timeframe
    Leiter R test was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    9
    8
    Units: integer
        arithmetic mean (standard deviation)
    6.82 ± 1.2
    0.94 ± 1.7
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.163
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in Leiter R test score - Repeated pattern

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    End point title
    		 Change from baseline in Leiter R test score - Repeated pattern
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.30 of the CSR
    End point type
    Secondary
    End point timeframe
    Leiter R test was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    9
    8
    Units: integer
        arithmetic mean (standard deviation)
    5.35 ± 0.75
    0.22 ± 0.97
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.544
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in Leiter R test score - Sequential order

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    End point title
    		 Change from baseline in Leiter R test score - Sequential order
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.31 of the CSR
    End point type
    Secondary
    End point timeframe
    Leiter R test was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    9
    8
    Units: integer
        arithmetic mean (standard deviation)
    4.85 ± 1.42
    0.63 ± 1.01
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.125
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in Leiter R test score - Total equivalence age 1

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    End point title
    		 Change from baseline in Leiter R test score - Total equivalence age 1
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.32 of the CSR
    End point type
    Secondary
    End point timeframe
    Leiter R test was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: integer
        arithmetic mean (standard deviation)
    5.63 ± 1.23
    0.46 ± 0.49
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    End evaluation v Baseline
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.022
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in audiometric best ear bone conduction

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    End point title
    		 Change from baseline in audiometric best ear bone conduction
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.33 of the CSR
    End point type
    Secondary
    End point timeframe
    Hearing test was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: Decibel
        arithmetic mean (standard deviation)
    50.72 ± 11.91
    -3.8 ± 9.78
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.277
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in audiometric left ear air conduction

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    End point title
    		 Change from baseline in audiometric left ear air conduction
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.34 of the CSR
    End point type
    Secondary
    End point timeframe
    Hearing test was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: Decibel
        arithmetic mean (standard deviation)
    61.1 ± 16.86
    -4.36 ± 8.42
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    End evaluation v Baseline
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.159
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in audiometric right ear air conduction

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    End point title
    		 Change from baseline in audiometric right ear air conduction
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.35 of the CSR
    End point type
    Secondary
    End point timeframe
    Hearing test was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: decibel
        arithmetic mean (standard deviation)
    59.35 ± 18.83
    -4.57 ± 6.16
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.057
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in CHAQ - pain on VAS

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    End point title
    		 Change from baseline in CHAQ - pain on VAS
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.37 of the CSR
    End point type
    Secondary
    End point timeframe
    CHAQ was administered at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    7
    Units: mm
        arithmetic mean (standard deviation)
    14 ± 17.31
    3.57 ± 16.06
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    End evaluation v Baseline
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.578
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in CHAQ - general evaluation on VAS

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    End point title
    		 Change from baseline in CHAQ - general evaluation on VAS
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.38 of the CSR
    End point type
    Secondary
    End point timeframe
    CHAQ was administered at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    9
    8
    Units: mm
        arithmetic mean (standard deviation)
    23.44 ± 21.33
    -3.13 ± 20.07
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.673
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in MRI ADC grey matter

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    End point title
    		 Change from baseline in MRI ADC grey matter
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.39 of the CSR
    End point type
    Secondary
    End point timeframe
    MRI was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: mm2/sec
        arithmetic mean (standard deviation)
    802.6 ± 39.4
    -20.44 ± 62.9
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.358
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in MRI ADC standard

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    End point title
    		 Change from baseline in MRI ADC standard
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.40 of the CSR
    End point type
    Secondary
    End point timeframe
    MRI was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: mm2/sec
        arithmetic mean (standard deviation)
    864 ± 89.94
    -9.44 ± 54.04
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.614
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in MRI ADC white matter

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    End point title
    		 Change from baseline in MRI ADC white matter
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.41 of the CSR
    End point type
    Secondary
    End point timeframe
    MRI was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: mm2/sec
        arithmetic mean (standard deviation)
    911.4 ± 112.77
    48.44 ± 88.58
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.139
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in MRS mannose complex visual grey matter

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    End point title
    		 Change from baseline in MRS mannose complex visual grey matter
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.42 of the CSR
    End point type
    Secondary
    End point timeframe
    MRS was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: ppm
        arithmetic mean (standard deviation)
    1.9 ± 0.74
    -0.33 ± 0.5
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.081
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in MRS mannose complex visual standard

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    End point title
    		 Change from baseline in MRS mannose complex visual standard
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.43 of the CSR
    End point type
    Secondary
    End point timeframe
    MRS was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: ppm
        arithmetic mean (standard deviation)
    1.67 ± 1.12
    0 ± 0.53
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in MRS mannose complex visual white matter

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    End point title
    		 Change from baseline in MRS mannose complex visual white matter
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.44 of the CSR
    End point type
    Secondary
    End point timeframe
    MRS was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: ppm
        arithmetic mean (standard deviation)
    1.8 ± 1.14
    -0.22 ± 0.67
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.347
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in MRS numerical mannose complex index grey matter

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    End point title
    		 Change from baseline in MRS numerical mannose complex index grey matter
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.45 of the CSR
    End point type
    Secondary
    End point timeframe
    MRS was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: ppm
        arithmetic mean (standard deviation)
    1 ± 0.51
    -0.06 ± 0.28
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    End evaluation v Baseline
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.54
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in MRS numerical mannose complex index standard

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    End point title
    		 Change from baseline in MRS numerical mannose complex index standard
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value). See Table 14.2.1.46 of the CSR
    End point type
    Secondary
    End point timeframe
    MRS was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: ppm
        arithmetic mean (standard deviation)
    1 ± 0.26
    -0.02 ± 0.29
    Statistical analysis title
    		 End of LAMAN04 vs Baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.839
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline in MRS numerical mannose complex index white matter

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    End point title
    		 Change from baseline in MRS numerical mannose complex index white matter
    End point description
    Baseline data for efficacy endpoints was recorded in the rhLAMAN-02 trial (the last value available before first dosing in rhLAMAN-02 was always used as the baseline value).
    End point type
    Secondary
    End point timeframe
    MRS was performed at baseline (rhLAMAN-02 Visit 2), at interim evaluation (Visit 13a, month 3), and at rhLAMAN-04 evaluation (Visit 26a, month 6).
    End point values
    		 Baseline End evaluation
    Number of subjects analysed
    10
    9
    Units: ppm
        arithmetic mean (standard deviation)
    0.99 ± 0.39
    0.04 ± 0.29
    Statistical analysis title
    		 End evaluation vs baseline
    Statistical analysis description
    End evaluation is made at Visit 26a of the LAMAN04 study
    Comparison groups
    Baseline v End evaluation
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.733
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE were recorded at interim evaluation (Visit 13a, month 12), at each dose visit (Visits 2-88), at rhLAMAN-04 evaluation (Visit 26a, month 18) and at Visit 89 (end of trial).
    Adverse event reporting additional description
    The reporting was based on the full analysis set (FAS) and the safety analysis set (the safety analysis set was defined as all patients exposed to at least one dose of IMP) and included all 10 patients who initiated treatment with Lamazym in the rhLAMAN-02 trial, and out of which 9 patients continued into the rhLAMAN-04 trial.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Safety analysis set
    Reporting group description
    		 The safety analysis set was defined as all patients exposed to at least one dose of IMP) and included all 10 patients who initiated treatment with Lamazym in the rhLAMAN-02 trial, and out of which 9 patients continued into the rhLAMAN-04 trial

    Serious adverse events
    		 Safety analysis set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    Loss of consciousness
    Additional description: An SAE of loss of consciousness occurred during the rhLAMAN-04 trial 14 months after start of treatment. It was severe and assessed by the investigator to be possibly related to trial drug.
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Safety analysis set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    Injury, poisoning and procedural complications
    Excoriation
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    3
    Contusion
         subjects affected / exposed
    3 / 9 (33.33%)
         occurrences all number
    6
    Wound
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Procedural pain
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    3
    Arthropod bite
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Procedural headache
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Open wound
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Ligament sprain
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Joint dislocation
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Application site erythema
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Foreign body in eye
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 9 (44.44%)
         occurrences all number
    4
    Dizziness
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    2
    Loss of consciousness
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Epilepsy
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 9 (33.33%)
         occurrences all number
    4
    Malaise
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Injection site pain
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Middle ear inflammation
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Eye disorders
    Eye infection
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Abdominal pain upper
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Tooth loss
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Dysphonia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Aggression
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Initial insomnia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    5
    Pain in extremity
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Myalgia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    2
    Tendon calcification
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Osteochondrosis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Joint instability
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 9 (88.89%)
         occurrences all number
    17
    Gastroenteritis
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Bronchitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Fungal infection
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Herpes simplex
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Wound infection
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Tonsillitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Laryngitis
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Aug 2012
    The period subjects will receive one dose of enzyme every week passes from 6 months to 10 months. - Continuation of the treatment passes from a total of 30 ± 4 weeks to a total of 40 ± 6 weeks. So that the EOT is numbered Visit #47 instead of Visit #35 - The dose visits becomes numbered 2-46 instead of 2-34.
    13 Nov 2012
    - The period subjects will receive one dose of enzyme every week passes from 6 months to 16 months. - Continuation of the treatment passes from a total of 30 ± 4 weeks to a total of 72 weeks. So that the EOT is numbered Visit #73 instead of Visit #35 - The dose visits becomes numbered 2-72 instead of 2-34.
    16 Apr 2013
    The period subjects will receive one dose of enzyme every week passes from 6 months to 20 months. - Continuation of the treatment passes from a total of 30 ± 4 weeks to a total of 88 weeks. So that the EOT is numbered Visit #89 instead of Visit #35 - The dose visits becomes numbered 2-89 instead of 2-34.

    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.
    No caveats or limitations are applicable to this summary of the results
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