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    Clinical Trial Results:
    A single center, randomized, open-label, multiple-dose study of the efficacy and long-term safety of rhLAMAN (recombinant human alpha-mannosidase or Lamazym) for the treatment of patients with alpha-mannosidosis

    Summary
    EudraCT number
    		 2010-022085-26
    Trial protocol
    		 DK  
    Global end of trial date
    26 Jan 2012

    Results information
    Results version number
    		 v2(current)
    This version publication date
    29 Jul 2016
    First version publication date
    09 Aug 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction of Sponsor organisation name and address.

    Trial information

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    Trial identification
    Sponsor protocol code
    rhLAMAN-03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01285700
    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 Spa, clinicaltrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency, Chiesi Farmaceutici Spa, 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
    Interim
    Date of interim/final analysis
    26 Jan 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jan 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jan 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • Define effective dose based on evaluation of efficacy of rhLAMAN (Lamazym) from baseline on: The biochemical markers , The clinical parameters • To evaluate the long-term safety profile of rhLAMAN (Lamazym)
    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
    24 Jan 2011
    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
    		 After written approval from the IEC was obtained, the investigator asked the participants in the phase 1 (rhLAMAN-02) trial whether they wanted to continue in this subsequent trial. All participating patients were recruited at Copenhagen University Hospital, Denmark.

    Pre-assignment
    Screening details
    		 All 10 patients from the previous trial (rhLAMAN-02) continued into this trial. They were screened, and subsequently randomized. No patients failed screening. One patient (25 U/kg) was withdrawn from treatment and subsequently withdrawn from the trial.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label trial and remained open-label to all staff involved both at the sponsor and Larix.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lamazym 25 U/kg
    Arm description
    		 The patients were allocated to study treatment by randomization. In the previous trial (rhLAMAN-02) patients were stratified to 5 different dose levels. The patients con-tinued from the rhLAMAN-02 trial into the rhLAMAN-03 trial. The dose levels were handled as blocks in the rhLAMAN-03 randomization. I.e. one patient from each dose level in this trial was randomized to 25 U/kg and 50 U/kg, respectively.
    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
    Lamazym at dose levels of 25 U/kg or 50 U/kg administered as intravenous (i.v.) infusions. The patients received i. v. infusions every week, for a total of 55 infusions (Visits 2-56).

    Arm title
    		 Lamazym 50 U/kg
    Arm description
    		 The patients were allocated to study treatment by randomization. In the previous trial (rhLAMAN-02) patients were stratified to 5 different dose levels. The patients continued from the rhLAMAN-02 trial into the rhLAMAN-03 trial. The dose levels were handled as blocks in the rhLAMAN-03 randomization. I.e. one patient from each dose level in this trial was randomized to 25 U/kg and 50 U/kg, respectively.
    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
    Lamazym at dose levels of 25 U/kg or 50 U/kg administered as intravenous (i.v.) infusions. The patients received i. v. infusions every week, for a total of 55 infusions (Visits 2-56).

    Number of subjects in period 1
    		Lamazym 25 U/kg Lamazym 50 U/kg
    Started
    5
    5
    Completed
    4
    5
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lamazym 25 U/kg
    Reporting group description
    		 The patients were allocated to study treatment by randomization. In the previous trial (rhLAMAN-02) patients were stratified to 5 different dose levels. The patients con-tinued from the rhLAMAN-02 trial into the rhLAMAN-03 trial. The dose levels were handled as blocks in the rhLAMAN-03 randomization. I.e. one patient from each dose level in this trial was randomized to 25 U/kg and 50 U/kg, respectively.

    Reporting group title
    Lamazym 50 U/kg
    Reporting group description
    		 The patients were allocated to study treatment by randomization. In the previous trial (rhLAMAN-02) patients were stratified to 5 different dose levels. The patients continued from the rhLAMAN-02 trial into the rhLAMAN-03 trial. The dose levels were handled as blocks in the rhLAMAN-03 randomization. I.e. one patient from each dose level in this trial was randomized to 25 U/kg and 50 U/kg, respectively.

    Reporting group values
    		 Lamazym 25 U/kg Lamazym 50 U/kg Total
    Number of subjects
    		 5 5 10
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 2 2 4
        Adolescents (12-17 years)
    		 3 3 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.7 ± 3.6 12.5 ± 4.4 -
    Gender categorical
    Units: Subjects
        Female
    		 1 2 3
        Male
    		 4 3 7

    End points

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    End points reporting groups
    Reporting group title
    Lamazym 25 U/kg
    Reporting group description
    		 The patients were allocated to study treatment by randomization. In the previous trial (rhLAMAN-02) patients were stratified to 5 different dose levels. The patients con-tinued from the rhLAMAN-02 trial into the rhLAMAN-03 trial. The dose levels were handled as blocks in the rhLAMAN-03 randomization. I.e. one patient from each dose level in this trial was randomized to 25 U/kg and 50 U/kg, respectively.

    Reporting group title
    Lamazym 50 U/kg
    Reporting group description
    		 The patients were allocated to study treatment by randomization. In the previous trial (rhLAMAN-02) patients were stratified to 5 different dose levels. The patients continued from the rhLAMAN-02 trial into the rhLAMAN-03 trial. The dose levels were handled as blocks in the rhLAMAN-03 randomization. I.e. one patient from each dose level in this trial was randomized to 25 U/kg and 50 U/kg, respectively.

    Primary: Change from baseline in serum oligasaccharide concentration

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    End point title
    		 Change from baseline in serum oligasaccharide concentration
    End point description
    For oligosaccharides in serum, urine and CSF a decrease in concentration was considered as an improvement for the patients and a biomarker for biochemical efficacy of Lamazym.
    End point type
    Primary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: μmol/L
        arithmetic mean (full range (min-max))
    3.5 (3 to 5)
    2.4 (2 to 3)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.085
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.47
         upper limit
    		 0.21
    Notes
    [1] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Primary: Change from baseline in urine oligasaccharide concentration

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    End point title
    		 Change from baseline in urine oligasaccharide concentration
    End point description
    End point type
    Primary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: μmol/L
        arithmetic mean (full range (min-max))
    402.25 (245 to 716)
    297.6 (185 to 427)
    Statistical analysis title
    		 Lamazym 50 U/Kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.426
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -103.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -399.41
         upper limit
    		 192.87
    Notes
    [2] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Primary: Change from baseline in CSF oligosaccharides

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    End point title
    		 Change from baseline in CSF oligosaccharides
    End point description
    End point type
    Primary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: μmol/L
        arithmetic mean (full range (min-max))
    6.25 (5 to 7)
    10.8 (7 to 14)
    Statistical analysis title
    		 Lamazym 50 U/Kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.033
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    5.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 9.45
    Notes
    [3] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Primary: Change from baseline in CSF albumin

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    End point title
    		 Change from baseline in CSF albumin
    End point description
    End point type
    Primary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: 10E-3
        arithmetic mean (full range (min-max))
    14.35 (4 to 39)
    5.42 (2 to 10)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.296
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -9.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.39
         upper limit
    		 10.3
    Notes
    [4] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Primary: Change from baseline in CSF-GFAp

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    End point title
    		 Change from baseline in CSF-GFAp
    End point description
    End point type
    Primary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: ng/L
        arithmetic mean (full range (min-max))
    850 (420 to 11130)
    854 (600 to 1260)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 50 U/kg v Lamazym 25 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.282
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -109.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -335.24
         upper limit
    		 116.78
    Notes
    [5] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Primary: Change from baseline in CSF-glucose

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    End point title
    		 Change from baseline in CSF-glucose
    End point description
    End point type
    Primary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: mmol/L
        arithmetic mean (full range (min-max))
    3 (3 to 3)
    3 (3 to 3)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.741
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 0.47
    Notes
    [6] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Primary: Change from baseline in CSF immunoglobulin G-index

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    End point title
    		 Change from baseline in CSF immunoglobulin G-index
    End point description
    End point type
    Primary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.re.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: digit
        arithmetic mean (full range (min-max))
    1 (1 to 1)
    0.522 (0 to 1)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.187
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.43
         upper limit
    		 0.1
    Notes
    [7] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Primary: Change from baseline in CSF immunoglobulin G

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    End point title
    		 Change from baseline in CSF immunoglobulin G
    End point description
    End point type
    Primary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: g/L
        arithmetic mean (full range (min-max))
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.291
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.11
    Notes
    [8] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Primary: Change from baseline in CSF NFL

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    End point title
    		 Change from baseline in CSF NFL
    End point description
    End point type
    Primary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: ng/L
        arithmetic mean (full range (min-max))
    690 (410 to 1180)
    616 (340 to 820)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.692
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    29.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -142.2
         upper limit
    		 200.31
    Notes
    [9] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Primary: Change from baseline in CSF protein

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    End point title
    		 Change from baseline in CSF protein
    End point description
    End point type
    Primary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: g/L
        arithmetic mean (full range (min-max))
    1.13 (0 to 3)
    0.388 (0 to 1)
    Statistical analysis title
    		 Lamzym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.302
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.41
         upper limit
    		 0.89
    Notes
    [10] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Primary: Change from baseline in CSF erythrocytes

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    End point title
    		 Change from baseline in CSF erythrocytes
    End point description
    End point type
    Primary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: 10E6/L
        arithmetic mean (full range (min-max))
    358.5 (0 to 749)
    28.6 (0 to 143)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.275
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (net)
    Point estimate
    -202.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -614.86
         upper limit
    		 209.95
    Notes
    [11] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Primary: Change from baseline in CSF tau

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    End point title
    		 Change from baseline in CSF tau
    End point description
    End point type
    Primary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: ng/L
        arithmetic mean (full range (min-max))
    283.25 (103 to 404)
    505.8 (384 to 613)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 50 U/kg v Lamazym 25 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.158
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    110.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.54
         upper limit
    		 279.13
    Notes
    [12] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Primary: Change from baseline in CSF leukocytes

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    End point title
    		 Change from baseline in CSF leukocytes
    End point description
    End point type
    Primary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: 10E6/L
        arithmetic mean (full range (min-max))
    0 (0 to 0)
    1.2 (0 to 6)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.405
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (net)
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 4.96
    Notes
    [13] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Secondary: Change frm baseline in MRI ADC grey matter

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    End point title
    		 Change frm baseline in MRI ADC grey matter
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: mm2/sec
        arithmetic mean (full range (min-max))
    764 (742 to 812)
    823.6 (735 to 1031)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.364
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    65.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -98.46
         upper limit
    		 230.26
    Notes
    [14] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: mm2/sec
        arithmetic mean (full range (min-max))
    851 (808 to 893)
    866.6 (752 to 1055)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.246
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -21.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -62.21
         upper limit
    		 19.35
    Notes
    [15] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: mm2/sec
        arithmetic mean (full range (min-max))
    973.25 (896 to 1056)
    981.6 (840 to 1085)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.487
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -40.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -173.99
         upper limit
    		 93.14
    Notes
    [16] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: ppm
        arithmetic mean (full range (min-max))
    1 (1 to 1)
    2 (1 to 3)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 50 U/kg v Lamazym 25 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.777
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.66
         upper limit
    		 1.3
    Notes
    [17] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: ppm
        arithmetic mean (full range (min-max))
    1 (0 to 3)
    2 (1 to 3)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.787
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 1.01
    Notes
    [18] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: digit
        arithmetic mean (full range (min-max))
    1 (1 to 1)
    1.106 (1 to 2)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 50 U/kg v Lamazym 25 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.8
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 0.26
    Notes
    [19] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: digit
        arithmetic mean (full range (min-max))
    1 (1 to 1)
    1 (1 to 1)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazyn 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.876
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.42
         upper limit
    		 0.37
    Notes
    [20] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

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

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    End point title
    		 Change form baseline in MRS numerical mannose complex index white matter
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    3
    5
    Units: digit
        arithmetic mean (full range (min-max))
    1 (1 to 1)
    1 (1 to 2)
    Statistical analysis title
    		 lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.66
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 0.57
    Notes
    [21] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: ppm
        arithmetic mean (full range (min-max))
    1 (0 to 2)
    1.8 (0 to 3)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Statistical analysis description
    The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.451
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 1.54

    Secondary: Change from baseline in gait step lenghth

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    End point title
    		 Change from baseline in gait step lenghth
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: cm
        arithmetic mean (full range (min-max))
    1 (1 to 1)
    0.523 (0 to 1)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    P-value
    		 = 0.003
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 -0.04
    Notes
    [22] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Secondary: Change from baseline in gait step width

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    End point title
    		 Change from baseline in gait step width
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: cm
        arithmetic mean (full range (min-max))
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.285
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.02
    Notes
    [23] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Secondary: Change from baseline in gait cadence

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    End point title
    		 Change from baseline in gait cadence
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: rpm
        arithmetic mean (full range (min-max))
    116 (104 to 125)
    126.4 (106 to 169)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 50 U/kg v Lamazym 25 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    P-value
    		 = 0.742
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.56
         upper limit
    		 20.66
    Notes
    [24] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Secondary: Change from baseline in gait velocity

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    End point title
    		 Change from baseline in gait velocity
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: m/sec
        arithmetic mean (full range (min-max))
    1 (1 to 1)
    1 (1 to 1)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 0.542
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.18
    Notes
    [25] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Secondary: Change from basline in BOT2

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    End point title
    		 Change from basline in BOT2
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: integer
        arithmetic mean (full range (min-max))
    31.25 (25 to 40)
    20.4 (0 to 35)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    P-value
    		 = 0.793
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.13
         upper limit
    		 11.43
    Notes
    [26] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: integer
        arithmetic mean (full range (min-max))
    25.5 (17 to 33)
    16.2 (0 to 28)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 50 U/kg v Lamazym 25 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.135
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.47
         upper limit
    		 1.12
    Notes
    [27] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: integer
        arithmetic mean (full range (min-max))
    20 (18 to 24)
    15.6 (2 to 26)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [28]
    P-value
    		 = 0.498
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.09
         upper limit
    		 2.77
    Notes
    [28] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: integer
        arithmetic mean (full range (min-max))
    30.75 (26 to 36)
    15.2 (2 to 28)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    P-value
    		 = 0.155
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -6.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16
         upper limit
    		 3.22
    Notes
    [29] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: integer
        arithmetic mean (full range (min-max))
    15.5 (9 to 20)
    13 (2 to 20)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 50 U/kg v Lamazym 25 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.999
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.36
         upper limit
    		 4.35

    Secondary: Change from baseline in BOT2 balance

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    End point title
    		 Change from baseline in BOT2 balance
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: integer
        arithmetic mean (full range (min-max))
    16.5 (10 to 24)
    12.8 (1 to 20)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [30]
    P-value
    		 = 0.661
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.24
         upper limit
    		 4.94
    Notes
    [30] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: integer
        arithmetic mean (full range (min-max))
    19 (12 to 23)
    15.2 (0 to 24)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    P-value
    		 = 0.749
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.07
         upper limit
    		 3.85
    Notes
    [31] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: integer
        arithmetic mean (full range (min-max))
    7.167 (7 to 8)
    6.133 (4 to 8)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [32]
    P-value
    		 = 0.088
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.87
         upper limit
    		 0.17
    Notes
    [32] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: integer
        arithmetic mean (full range (min-max))
    7.458 (7 to 9)
    5.367 (3 to 8)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    P-value
    		 = 0.261
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.81
         upper limit
    		 1.25
    Notes
    [33] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: integer
        arithmetic mean (full range (min-max))
    6.625 (6 to 8)
    6.367 (5 to 9)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [34]
    P-value
    		 = 0.962
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.17
         upper limit
    		 1.12
    Notes
    [34] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: integer
        arithmetic mean (full range (min-max))
    5.729 (5 to 7)
    4.983 (3 to 8)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 50 U/kg v Lamazym 25 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 = 0.614
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.91
         upper limit
    		 0.59
    Notes
    [35] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: integer
        arithmetic mean (full range (min-max))
    5.979 (5 to 7)
    5.667 (5 to 7)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 50 U/kg v Lamazym 25 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [36]
    P-value
    		 = 0.294
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.68
         upper limit
    		 0.63
    Notes
    [36] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    4
    Units: integer
        arithmetic mean (full range (min-max))
    8.813 (7 to 11)
    7.188 (7 to 8)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 = 0.263
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.18
         upper limit
    		 1.43
    Notes
    [37] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

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

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    End point title
    		 Change from baseline in Leiter R score - Total equivalence age
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: integer
        arithmetic mean (full range (min-max))
    6.583 (6 to 7)
    5.6 (3 to 8)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [38]
    P-value
    		 = 0.011
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.83
         upper limit
    		 -0.16
    Notes
    [38] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Secondary: Change from baseline in pulmonary FVC

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    End point title
    		 Change from baseline in pulmonary FVC
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    3
    5
    Units: liters
        arithmetic mean (full range (min-max))
    2.95 (2 to 4)
    2.302 (1 to 3)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 other [39]
    P-value
    		 = 0.901
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.23
         upper limit
    		 1.36
    Notes
    [39] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Secondary: Change from baseline in pulmonary FVC - percent

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    End point title
    		 Change from baseline in pulmonary FVC - percent
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    3
    5
    Units: percent
        arithmetic mean (full range (min-max))
    93.667 (88 to 98)
    81.4 (51 to 111)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 50 U/kg v Lamazym 25 U/kg
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 other [40]
    P-value
    		 = 0.532
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -11.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -53.91
         upper limit
    		 31.6
    Notes
    [40] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Secondary: Change from baseline in FEV

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    End point title
    		 Change from baseline in FEV
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    3
    5
    Units: liters
        arithmetic mean (full range (min-max))
    2.697 (2 to 4)
    2.188 (1 to 3)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.847
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.06
         upper limit
    		 1.24

    Secondary: Change from baseline in pulmonary FEV - percent

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    End point title
    		 Change from baseline in pulmonary FEV - percent
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    3
    5
    Units: percent
        arithmetic mean (full range (min-max))
    92.333 (86 to 102)
    83.4 (55 to 115)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamzym 25 U/kg
    Comparison groups
    Lamazym 50 U/kg v Lamazym 25 U/kg
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 other [41]
    P-value
    		 = 0.639
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -8.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -52.64
         upper limit
    		 35.55
    Notes
    [41] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Secondary: 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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    3
    5
    Units: L/sec
        arithmetic mean (full range (min-max))
    5.277 (4 to 6)
    4.116 (1 to 6)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 other [42]
    P-value
    		 = 0.967
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.22
         upper limit
    		 2.15
    Notes
    [42] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Secondary: Change from baseline in pulmonary maximal inspiratory pressure

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    End point title
    		 Change from baseline in pulmonary maximal inspiratory pressure
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    3
    2
    Units: cm H20
        arithmetic mean (full range (min-max))
    35.867 (21 to 45)
    20.425 (20 to 21)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 50 U/kg v Lamazym 25 U/kg
    Number of subjects included in analysis
    5
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.037
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -13.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.37
         upper limit
    		 -2.03

    Secondary: Change from baseline in pulmonary total lung capacity

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    End point title
    		 Change from baseline in pulmonary total lung capacity
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    2
    1
    Units: liters
        arithmetic mean (full range (min-max))
    3.36 (3 to 4)
    5 (5 to 5)
    No statistical analyses for this end point

    Secondary: Change from baseline in pulmonary total lung capacity - percent

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    End point title
    		 Change from baseline in pulmonary total lung capacity - percent
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    2
    1
    Units: percent
        arithmetic mean (full range (min-max))
    29 (25 to 33)
    38 (38 to 38)
    No statistical analyses for this end point

    Secondary: Change from baseline in pulmonary diffusion capacity

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    End point title
    		 Change from baseline in pulmonary diffusion capacity
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    2
    1
    Units: mmmol/L/kPa
        arithmetic mean (full range (min-max))
    5.995 (5 to 7)
    6 (6 to 6)
    No statistical analyses for this end point

    Secondary: Change from baseline in pulmonary S Raw

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    End point title
    		 Change from baseline in pulmonary S Raw
    End point description
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    2
    Units: kPa
        arithmetic mean (full range (min-max))
    1 (1 to 1)
    1 (1 to 1)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 other [43]
    P-value
    		 = 0.126
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0.92
    Notes
    [43] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: dB
        arithmetic mean (full range (min-max))
    50.7 (14 to 73)
    63.52 (51 to 73)
    Statistical analysis title
    		 lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [44]
    P-value
    		 = 0.105
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    10.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.01
         upper limit
    		 24.32
    Notes
    [44] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: dB
        arithmetic mean (full range (min-max))
    51.525 (21 to 70)
    59.02 (45 to 71)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 50 U/kg v Lamazym 25 U/kg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [45]
    P-value
    		 = 0.14
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    7.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.18
         upper limit
    		 17.62
    Notes
    [45] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    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
    End point type
    Secondary
    End point timeframe
    This parameter was measured at baseline and at Visit 13a and Visit 26a. Only data on "end evaluation" (26th week) are reported here.
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    4
    Units: dB
        arithmetic mean (full range (min-max))
    52.2 (35 to 65)
    50.275 (41 to 65)
    Statistical analysis title
    		 Lamazym 50 U/kg vs Lamazym 25 U/kg
    Comparison groups
    Lamazym 25 U/kg v Lamazym 50 U/kg
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 other [46]
    P-value
    		 = 0.287
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -4.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.81
         upper limit
    		 5.07
    Notes
    [46] - The study aims to define effective dose (dose ranging) based on evaluation of efficacy of Lamazym from baseline, so it has an explorative nature.

    Secondary: AUCcorr

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    End point title
    		 AUCcorr
    End point description
    End point type
    Secondary
    End point timeframe
    At Visit 13a (interim data).
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    2
    5
    Units: h*μg/L
        arithmetic mean (standard deviation)
    216284 ± 48875
    401086 ± 113064
    No statistical analyses for this end point

    Secondary: AUC

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    End point title
    		 AUC
    End point description
    End point type
    Secondary
    End point timeframe
    At Visit 13 a(interim data).
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: h*μg/L
        arithmetic mean (standard deviation)
    159120 ± 106004
    444046 ± 139984
    No statistical analyses for this end point

    Secondary: AUCt

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    End point title
    		 AUCt
    End point description
    End point type
    Secondary
    End point timeframe
    At Visit 13a (interim data).
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: h*μg/L
        arithmetic mean (standard deviation)
    143925 ± 99419
    407623 ± 140646
    No statistical analyses for this end point

    Secondary: AUCextrap

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    End point title
    		 AUCextrap
    End point description
    End point type
    Secondary
    End point timeframe
    At Visit 13a (interim data).
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: percent
        arithmetic mean (standard deviation)
    11.7 ± 5.4
    9 ± 4.4
    No statistical analyses for this end point

    Secondary: Cmax

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    End point title
    		 Cmax
    End point description
    End point type
    Secondary
    End point timeframe
    At Visit 13a (interim data).
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: μg/L
        arithmetic mean (standard deviation)
    8858 ± 2700
    17260 ± 2051
    No statistical analyses for this end point

    Secondary: CL

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    End point title
    		 CL
    End point description
    End point type
    Secondary
    End point timeframe
    At Visit 13a (interim data).
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: L/h/kg
        arithmetic mean (standard deviation)
    0.0136 ± 0.0189
    0.004 ± 0.0014
    No statistical analyses for this end point

    Secondary: t1/2

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    End point title
    		 t1/2
    End point description
    End point type
    Secondary
    End point timeframe
    At Visit 13a (interim data).
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: hours
        arithmetic mean (standard deviation)
    24.4 ± 18.3
    43.7 ± 16.4
    No statistical analyses for this end point

    Secondary: Vz

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    End point title
    		 Vz
    End point description
    End point type
    Secondary
    End point timeframe
    At Visit 13a (interim data).
    End point values
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Number of subjects analysed
    4
    5
    Units: L/kg
        arithmetic mean (standard deviation)
    0.172 ± 0.023
    0.232 ± 0.059
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Visit 2 to Visit 57 (last visit)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Lamazym 25 U/kg
    Reporting group description
    		 The patients were allocated to study treatment by randomization. In the previous trial (rhLAMAN-02) patients were stratified to 5 different dose levels. The patients con-tinued from the rhLAMAN-02 trial into the rhLAMAN-03 trial. The dose levels were handled as blocks in the rhLAMAN-03 randomization. I.e. one patient from each dose level in this trial was randomized to 25 U/kg and 50 U/kg, respectively.

    Reporting group title
    Lamazym 50 U/kg
    Reporting group description
    		 The patients were allocated to study treatment by randomization. In the previous trial (rhLAMAN-02) patients were stratified to 5 different dose levels. The patients continued from the rhLAMAN-02 trial into the rhLAMAN-03 trial. The dose levels were handled as blocks in the rhLAMAN-03 randomization. I.e. one patient from each dose level in this trial was randomized to 25 U/kg and 50 U/kg, respectively.

    Serious adverse events
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Syncope
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Lamazym 25 U/kg Lamazym 50 U/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    5 / 5 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 5 (60.00%)
         occurrences all number
    1
    3
    Ear tube insertion
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    2
    Wisdom teeth removal
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Pyrexia
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    2
    Catheter site pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Chills
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Feeling hot
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Medical device pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    Hypersensitivity
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Seasonal allergy
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    Bronchitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    Sneezing
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Tracheitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Investigations
    Weight increased
         subjects affected / exposed
    3 / 5 (60.00%)
    3 / 5 (60.00%)
         occurrences all number
    4
    3
    White blood cells urine positive
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Excoriation
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 5 (40.00%)
         occurrences all number
    4
    7
    Post lumbar puncture syndrome
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    1
    Contusion
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Arthropod bite
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    Fall
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Head injury
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Infected bites
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Joint sprain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Tooth injury
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Wound
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 5 (40.00%)
         occurrences all number
    2
    7
    Confusional state
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Inner ear inflammation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    Eye disorders
    Eye infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Eye pruritus
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Ear infection
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    2
    Diarrhoea
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 5 (20.00%)
         occurrences all number
    3
    1
    Vomiting
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 5 (60.00%)
         occurrences all number
    0
    3
    Abdominal pain
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    Nausea
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Reflux gastritis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Herpes simplex
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Pain of skin
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 5 (40.00%)
         occurrences all number
    4
    2
    Arthralgia
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 5 (20.00%)
         occurrences all number
    3
    1
    Back pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 5 (100.00%)
    4 / 5 (80.00%)
         occurrences all number
    11
    7
    Gastroenteritis
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Viral infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Nov 2010
    • Addition of a pregnancy test in the post-menarche adolescent women at inclusion and throughout the trial • Reduction of the infusion rate from 1.5 mg/min to 0.5 mg/min protein • A time-interval was added for timing of PK measurements Changes were not expected to affect the objectives of the trial.
    01 Mar 2011
    • Due to patient convenience, the time point for PK sampling was moved from Visit 11 to 13a. This change was not expected to affect the outcome of the tests, as both original and change visits were performed after steady state was reached.
    26 Apr 2011
    • Due to a medication pause during the trial, a need for definition of procedures for terminating the trial before time (“early termination”) was needed and additions to Section 7.4 (Patient withdrawal) was added. Furthermore additional sections were added: Sections 7.4.1 (Pause with medication), 7.4.2 (Withdrawal of medication) and 7.4.3 (Withdrawal of all trial related procedures). The changes were not expected to affect the secondary objective (long-term safety) as the intention was to keep the patient in the trial and collect safety data from the subsequent visits.
    22 Jun 2011
    To avoid the patients should terminate their treatment between the present protocol and inclusion in the following phase 2b protocol, a continuation phase was added. The continuation phase extended the trial up to 12 months, with continuation of weekly dosing. Additionally the end evaluation at Visit 26a was moved one week, from Week 28 ± 2 to Week 29 ± 2 due to logistic reasons. The changes were not expected to affect the objectives of the trial.
    20 Dec 2011
    To avoid the patients should terminate their treatment between the present protocol and inclusion in the following phase 2b protocol, Amendment 5 introduced the possibility of, if necessary, extending the continuation phase introduced in Amendment 4 with additional 4 weeks (Visit 56). Further, the possibility of using a freeze dried batch of drug was introduced in case of shortage of drug supply.

    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 limitations or caveats are applicable to this summary.
    For support, Contact us.
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