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    Clinical Trial Results:
    A Phase 2/3, Open-Label, Repeat-Dose Study of the Pharmacokinetics, Efficacy, and Safety of ProMetic Plasminogen Intravenous Infusion in Subjects with Hypoplasminogenemia

    Summary
    EudraCT number
    		 2015-005490-20
    Trial protocol
    		 NO  
    Global end of trial date
    08 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 May 2021
    First version publication date
    29 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2002C011G
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02690714
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Prometic Biotherapeutics Inc.
    Sponsor organisation address
    1330 Piccard Drive, Suite 201, Rockville, United States, MD 20850
    Public contact
    Medical Officer, Prometic Biotherapeutics Inc., 301 549-9761, clinical@prometic.com
    Scientific contact
    Medical Officer, Prometic Biotherapeutics Inc., 301 549-9761, clinical@prometic.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To achieve an increase of individual trough plasminogen activity by at least an absolute 10% (i.e., 10 U/dL) from baseline during the 12 weeks of plasminogen replacement therapy in Segment 2; and to evaluate the efficacy of plasminogen replacement therapy on clinically evident or visible symptoms of hypoplasminogenia during the 48 weeks of dosing in Segments 2 and 3.
    Protection of trial subjects
    A Safety Monitoring Committee (SMC) composed of the sponsor’s Medical Monitor and an independent Medical Monitor reviewed study safety data biweekly during Segments 1 and 2, and periodically during Segment 3.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 May 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    United States: 12
    Worldwide total number of subjects
    15
    EEA total number of subjects
    3
    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)
    4
    Adolescents (12-17 years)
    2
    Adults (18-64 years)
    9
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 2 sites, 1 in the United States (US) and 1 in Norway. The first participant was screened in May 2016 and the last participant visit was in October 2018.

    Pre-assignment
    Screening details
    		 Subjects were screened for study eligibility within a period of no more than 21 days before the start of dosing.

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

    Arms
    Arm title
    		 Plasminogen (Human) Intravenous
    Arm description
    		 6.6 mg/kg Plasminogen (Human) Intravenous given every 2 to 4 days by a 10- to 30- minute intravenous infusion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ryplazim
    Investigational medicinal product code
    Other name
    Plasminogen (Human)
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    6.6 mg/kg given as a single dose in segment 1, and repeat doses in Segments 2 and 3

    Number of subjects in period 1
    		Plasminogen (Human) Intravenous
    Started
    15
    Segment 1
    9 [1]
    Segment 2
    15
    Segment 3
    15
    Segment 3 (Wk 48 - Completed)
    15
    Post Week-48
    12
    Completed
    10
    Not completed
    5
         Consent withdrawn by subject
    1
         Physician decision
    1
         Norway participants did not continue on post Wk48
    3
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Six participants skipped Segment 1 as they had PK data from Phase 1 study 2002C005G (allowed per protocol).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Plasminogen (Human) Intravenous
    Reporting group description
    		 6.6 mg/kg Plasminogen (Human) Intravenous given every 2 to 4 days by a 10- to 30- minute intravenous infusion

    Reporting group values
    		 Plasminogen (Human) Intravenous Total
    Number of subjects
    		 15 15
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 4 4
        Adolescents (12-17 years)
    		 2 2
        Adults (18-64 years)
    		 9 9
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 23.0 ± 13.05 -
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 4 4
    Race (NIH/OMB)
    Units: Subjects
        White
    		 15 15
    Race/Ethnicity, Customised
    Units: Subjects
        Hispanic/Latino
    		 1 1
        Non-Hispanic/Latino
    		 14 14
    Region of Enrollment
    Units: Subjects
        United States
    		 12 12
        Norway
    		 3 3
    Visible and Non-Visible Lesions by Participant
    Units: Subjects
        None
    		 4 4
        > = 1 Visible or non-visible lesion
    		 11 11
    Plasminogen Activity
    Units: Subjects
        Plasminogen activity <5-10%
    		 3 3
        Plasminogen activity 11-20%
    		 4 4
        Plasminogen activity 21-30%
    		 6 6
        Plasminogen activity 31-40%
    		 1 1
        Plasminogen activity 41-45%
    		 1 1
        Plasminogen activity >45%
    		 0 0
    Plasminogen antigen
    Units: Subjects
        Plasminogen antigen <0.5-3.0 mg/dL
    		 4 4
        Plasminogen antigen 3.1-6.0 mg/dL
    		 10 10
        Plasminogen antigen 6.1-2.0 mg/dL
    		 1 1
        Plasminogen antigen >20.0 mg/dL
    		 0 0
    Quality of Life Assessment
    For the Quality of Life (QOL) assessment, participants were asked to rate their overall QOL using an 11-point scale (0 = Non functioning, 10 = normal);the QOL scale was adapted from a scale developed by the American Chronic Pain Association
    Units: Subjects
        QOL score = 0
    		 0 0
        QOL score = 1
    		 0 0
        QOL score = 2
    		 0 0
        QOL score = 3
    		 0 0
        QOL score = 4
    		 0 0
        QOL score = 5
    		 0 0
        QOL score = 6
    		 1 1
        QOL score = 7
    		 3 3
        QOL score = 8
    		 1 1
        QOL score = 9
    		 1 1
        QOL score = 10
    		 9 9
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 60.37 ± 26.803 -
    Plasminogen Activity
    Plasminogen % activity is a measurement of functional plasminogen levels.
    Units: percent
        arithmetic mean (standard deviation)
    		 21.1 ± 10.83 -
    Plasminogen antigen
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 4.7 ± 3.7 -

    End points

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    End points reporting groups
    Reporting group title
    Plasminogen (Human) Intravenous
    Reporting group description
    		 6.6 mg/kg Plasminogen (Human) Intravenous given every 2 to 4 days by a 10- to 30- minute intravenous infusion

    Primary: Overall Clinical Success in Number and Size of Lesions as Measured by Photographic or Other Imaging Modality Depending on the Organ System Affected or Change in Afffected Organ Functionality at 48 Weeks

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    End point title
    		 Overall Clinical Success in Number and Size of Lesions as Measured by Photographic or Other Imaging Modality Depending on the Organ System Affected or Change in Afffected Organ Functionality at 48 Weeks [1]
    End point description
    Overall clinical success was defined as 50% of participants with visible or other measurable lesions achieving at least a 50% improvement in lesion number/size or functionality impact from baseline. Visible lesions were defined as dimensions could have been assed by medical imaging studies (eg, computed tomography, magnetic resonance imaging, ultrasound, etc) or functional assessments (eg, spirometry, audiogram, oximetry, etc.). Visible lesions that had both a length and width as measured by the 1mm scale, were referred to as "measurable lesions", and visible lesions that were too small to measure by the 1mm scale (length and/or width could not have been measured) were referred to as "non-measurable lesions".
    End point type
    Primary
    End point timeframe
    48 Weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Given the ultra-rarity of the disease and study design, all data were presented descriptively.
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15 [2]
    Units: Lesions
        Number of lesions analysed at baseline
    47
        Visible lesions at baseline
    32
        Non-Visible lesions at baseline
    15
        Total Visible/Non-Visible lesions resolved Wk 48
    34
        Total Visible/Non-Visible lesions improved Wk 48
    10
        Not applicable (not assessed) Wk 48
    3
    Notes
    [2] - All 15 participants were assessed, but only 11 had visible and/or non-visible lesions at baseline.
    No statistical analyses for this end point

    Primary: Number and Percentage of Participants Who Achieved the Target Plasminogen Activity Trough Levels for at Least 3 Measurements in 12 weeks During Segment 2

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    End point title
    		 Number and Percentage of Participants Who Achieved the Target Plasminogen Activity Trough Levels for at Least 3 Measurements in 12 weeks During Segment 2 [3]
    End point description
    Plasminogen activity is a measurement of functional plasminogen levels and is therefore the most accurate and specific method to quantify active Plasminogen (Human) Intravenous concentration in participant's plasma. Primary endpoint success was defined as at least 80% of evaluable participants (ie, 8 or more) achieving the target trough levels for at least 3 measurements in 12 weeks. The target trough level was defined as an increase in plasminogen activity level of at least an absolute 10% (10 U/dL) from the participants individual baseline level.
    End point type
    Primary
    End point timeframe
    12 Weeks
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Given the ultra-rarity of the disease and study design, all data were presented descriptively.
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15
    Units: Participants
        Number of participants
    15
        Percentage of participants
    100
    No statistical analyses for this end point

    Secondary: Overall Clinical Success in Number and Size of Lesions as Measured by Photographic or Other Imaging Modality Depending on the Organ System Affected of Change in Affected Organ Functionality at 12 Weeks

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    End point title
    		 Overall Clinical Success in Number and Size of Lesions as Measured by Photographic or Other Imaging Modality Depending on the Organ System Affected of Change in Affected Organ Functionality at 12 Weeks
    End point description
    Overall clinical success was defined as 50% of participants with visible of other measurable lesions achieving at least a 50% improvement in lesion number/size of functionality impact from baseline. Visible lesions were defined as lesions that could be imaged and analysed with digital photography. Non-visible lesions were defined as lesions whose dimensions could have been assessed by medical imaging studies (eg, computed tomography, magnetic resonance imaging, ultrasound, etc) or functional assessments (eg, spirometry, audiogram, oximetry, etc). Visible lesions that were too small to measure by the 1mm scale (length and/or width could not have been measured) were referred to as "non-measurable lesions".
    End point type
    Secondary
    End point timeframe
    12 Weeks
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15 [4]
    Units: Number of Lesions
        Number of lesions analysed at baseline
    47
        Visible lesions at baseline
    32
        Non-visible lesions at baseline
    15
        Total Visible/Non-Visible lesions resolved Wk 12
    26
        Total Visible/Non-Visible lesions improved Wk 12
    14
        Total Visible/Non-Visible lesions unchanged Wk 12
    2
        Not applicable/Not assessed Wk 12
    5
    Notes
    [4] - All 15 participants were assessed, but only 11 had visible and/or non-visible lesions at baseline.
    No statistical analyses for this end point

    Secondary: Clinical Global Impression -Global Improvement (CGI-I) Scores at Week 12

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    End point title
    		 Clinical Global Impression -Global Improvement (CGI-I) Scores at Week 12
    End point description
    CGI-I scores are measured at 12 and 48 weeks after study drug treatment. The CGI-I scale is a single, clinician completed scale designed to capture the clinician's impression of the participant's disease improvement over time. For this scale, clinicians were asked to consider their experience in this population and rate the change relative to the participant's state at Baseline using a 7-point scale (1 = very much improved, 7 = very much worse).
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15
    Units: Participants
        CGI score 0 = Not assessed : Week 12
    0
        CGI score 1 = Very much improved : Week 12
    11
        CGI score 2 = Much improved : Week 12
    4
        CGI score 3 = Minimally improved : Week 12
    0
        CGI score 4 = No change : Week 12
    0
        CGI score 5 = Minimally worse : Week 12
    0
        CGI score 6= Much worse : Week 12
    0
        CGI score 7 = Very much worse : Week 12
    0
    No statistical analyses for this end point

    Secondary: Clinical Global Impression -Global Improvement (CGI-I) Scores at Week 48

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    End point title
    		 Clinical Global Impression -Global Improvement (CGI-I) Scores at Week 48
    End point description
    CGI-I scores are measured at 12 and 48 weeks after study drug treatment. The CGI-I scale is a single, clinician completed scale designed to capture the clinician's impression of the participant's disease improvement over time. For this scale, clinicians were asked to consider their experience in this population and rate the change relative to the participant's state at Baseline using a 7-point scale (1 = very much improved, 7 = very much worse).
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15
    Units: Participants
        CGI score 0 = Not assessed : Week 48
    0
        CGI score 1= Very much improved : Week 48
    13
        CGI score 2 = Much improved : Week 48
    2
        CGI score 3 = Minimally improved : Week 48
    0
        CGI score 4 = No change : Week 48
    0
        CGI score 5 = Minimally worse : Week 48
    0
        CGI score 6 = Much worse : Week 48
    0
        CGI score 7 = Very much worse : Week 48
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment

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    End point title
    		 Number of Participants With Improved Quality of Life (QOL) Score After 12 Weeks of Study Treatment
    End point description
    Quality of life score (QOL) was measured at baseline and at 12 and 48 weeks after study drug treatment. For the QOL assessment, participants were asked to rate their overall QOL using an 11-point scale (0 = non-functioning, 10 = normal). The QOL scale was adapted from a scale developed by the American Chronic Pain Association.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15
    Units: Participants
        QOL score = 0 : Week 12
    0
        QOL score = 1 : Week 12
    0
        QOL score = 2 : Week 12
    0
        QOL score = 3 : Week 12
    0
        QOL score = 4 : Week 12
    0
        QOL score = 5 : Week 12
    1
        QOL score = 6 : Week 12
    0
        QOL score = 7 : Week 12
    0
        QOL score = 8 : Week 12
    0
        QOL score = 9 : Week 12
    1
        QOL score = 10 : Week 12
    13
    No statistical analyses for this end point

    Secondary: Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment

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    End point title
    		 Number of Participants With Improved Quality of Life (QOL) Score After 48 Weeks of Study Treatment
    End point description
    Quality of life score (QOL) was measured at baseline and at 12 and 48 weeks after study drug treatment. For the QOL assessment, participants were asked to rate their overall QOL using an 11-point scale (0 = non-functioning, 10 = normal). The QOL scale was adapted from a scale developed by the American Chronic Pain Association.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15
    Units: Participants
        QOL score = 0 : Week 48
    0
        QOL score = 1 : Week 48
    0
        QOL score = 2 : Week 48
    0
        QOL score = 3 : Week 48
    0
        QOL score = 4 : Week 48
    0
        QOL score = 5 : Week 48
    1
        QOL score = 6 : Week 48
    0
        QOL score = 7 : Week 48
    0
        QOL score = 8 : Week 48
    0
        QOL score = 9 : Week 48
    1
        QOL score = 10 : Week 48
    13
    No statistical analyses for this end point

    Secondary: Plasminogen Activity Trough Levels between Week 2 and Week 120

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    End point title
    		 Plasminogen Activity Trough Levels between Week 2 and Week 120
    End point description
    Plasminogen activity trough levels were measured at Weeks 2, 4, 6, 8, 10, 12, 24, 36, 48, 60, 72, 84, 96, 108, and 120.
    End point type
    Secondary
    End point timeframe
    Week 2 to Week 120
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15
    Units: Percentage of Activity
    arithmetic mean (standard deviation)
        Week 2 (n=14)
    45.1 ± 15.05
        Week 4 (n=15)
    48.9 ± 14.56
        Week 6 (n=15)
    52.4 ± 11.45
        Week 8 (n=15)
    48.3 ± 17.43
        Week 10 (n=15)
    50.2 ± 12.39
        Week 12 (n=15)
    51.0 ± 12.01
        Week 24 (n=15)
    45.0 ± 12.88
        Week 36 (n=15)
    45.5 ± 13.18
        Week 48 (n=15)
    41.7 ± 16.99
        Week 60 (n=13)
    49.0 ± 8.88
        Week 72 (n=12)
    46.7 ± 10.97
        Week 84 (n=12)
    51.7 ± 20.76
        Week 96 (n=9)
    50.1 ± 20.08
        Week 108 (n=7)
    45.0 ± 25.19
        Week 120 (n=2)
    36.5 ± 12.02
    No statistical analyses for this end point

    Secondary: Plasminogen Antigen Trough Levels between Week 2 and Week 120

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    End point title
    		 Plasminogen Antigen Trough Levels between Week 2 and Week 120
    End point description
    Plasminogen antigen trough levels were measured at weeks 2, 4, 6, 8, 10, 12, 24, 36, 48, 60, 72, 84, 96, 108, and 120.
    End point type
    Secondary
    End point timeframe
    Week 2 to Week 120
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15
    Units: mg/dL
    arithmetic mean (standard deviation)
        Week 2 (n=14)
    6.550 ± 3.0457
        Week 4 (n=15)
    7.800 ± 3.8813
        Week 6 (n=15)
    7.268 ± 3.3155
        Week 8 (n=15)
    6.607 ± 3.0046
        Week 10 (n=15)
    9.460 ± 7.1543
        Week 12 (n=15)
    7.340 ± 2.9342
        Week 24 (n=15)
    5.913 ± 2.2181
        Week 36 (n=15)
    6.667 ± 2.7336
        Week 48 (n=15)
    6.973 ± 3.1299
        Week 60 (n=13)
    6.415 ± 1.7578
        Week 72 (n=12)
    6.083 ± 2.2851
        Week 84 (n=12)
    7.183 ± 3.8129
        Week 96 (n=9)
    7.656 ± 4.2030
        Week 108 (n=7)
    6.529 ± 4.0852
        Week 120 (n=2)
    6.550 ± 6.2933
    No statistical analyses for this end point

    Secondary: Half-life (t1/2) of Plasminogen Activity After First Dose and at Week 12

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    End point title
    		 Half-life (t1/2) of Plasminogen Activity After First Dose and at Week 12
    End point description
    t1/2 is time required for the plasma concentration of Plasminogen to decrease 50% in the final stages of its elimination
    End point type
    Secondary
    End point timeframe
    First dose and 12 weeks
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15
    Units: Hours
    arithmetic mean (standard deviation)
        Mean (SD) t1/2 of plasminogen after the first dose
    34 ± 11.73
        Mean (SD) t1/2 of plasminogen at week 12
    39.2 ± 6.22
    No statistical analyses for this end point

    Secondary: AUClast of Plasminogen Activity After the First Dose and at Week 12

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    End point title
    		 AUClast of Plasminogen Activity After the First Dose and at Week 12
    End point description
    AUCLast is the area under the plasma concentration-curve of Plasminogen from time 0 to the last measured concentration
    End point type
    Secondary
    End point timeframe
    First dose and 12 weeks
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15
    Units: hr*%
    arithmetic mean (standard deviation)
        Mean (SD) AUClast after first dose of plasminogen
    3063.6 ± 778.67
        Mean (SD) AUClast at Week 12
    4656.0 ± 1012.66
    No statistical analyses for this end point

    Secondary: Cmax of Plasminogen Activity After First Dose and at Week 12

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    End point title
    		 Cmax of Plasminogen Activity After First Dose and at Week 12
    End point description
    Cmax is the maximum plasma concentration of Plasminogen
    End point type
    Secondary
    End point timeframe
    First dose and 12 weeks
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15
    Units: % of plasminogen activity
    arithmetic mean (standard deviation)
        Mean (SD) Cmax of plasminogen after first dose
    95 ± 23.5
        Mean (SD) Cmax of plasminogen at Week 12
    125 ± 23.3
    No statistical analyses for this end point

    Secondary: Cl of Plasminogen Activity After First Dose and at Week 12

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    End point title
    		 Cl of Plasminogen Activity After First Dose and at Week 12
    End point description
    Cl is the volume of plasma cleared of Plasminogen per unit time
    End point type
    Secondary
    End point timeframe
    First dose and 12 weeks
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15
    Units: mL/hr/kg
    arithmetic mean (standard deviation)
        Mean (SD) Cl of plasminogen after first dose
    1.44 ± 0.460
        Mean (SD) Cl of plasminogen at Week 12
    0.92 ± 0.257
    No statistical analyses for this end point

    Secondary: AUCIinf of Plasminogen Activity After First Dose and at Week 12

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    End point title
    		 AUCIinf of Plasminogen Activity After First Dose and at Week 12
    End point description
    AUCinf is the area under the plasma concentration-curve of Plasminogen from time 0 extrapolated to infinity
    End point type
    Secondary
    End point timeframe
    First dose and 12 weeks
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15
    Units: hr*%
    arithmetic mean (standard deviation)
        Mean (SD) AUCinf of plasminogen after first dose
    3605.8 ± 1023.88
        Mean (SD) AUCinf of plasminogen at Week 12
    5731.8 ± 1431.70
    No statistical analyses for this end point

    Secondary: MRTlast for Plasminogen Activity After First Dose and at Week 12

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    End point title
    		 MRTlast for Plasminogen Activity After First Dose and at Week 12
    End point description
    MRTlast is the mean residence time of Plasminogen from time 0 to the last measured concentration
    End point type
    Secondary
    End point timeframe
    First dose and 12 weeks
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15
    Units: hours
    arithmetic mean (standard deviation)
        Mean (SD) MRTlast of plasminogen after first dose
    30.6 ± 3.22
        Mean (SD) MRTlast of plasminogen at Week 12
    33.5 ± 1.60
    No statistical analyses for this end point

    Secondary: Vss for Plasminogen Activity After First Dose and at Week 12

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    End point title
    		 Vss for Plasminogen Activity After First Dose and at Week 12
    End point description
    Vss is the apparent volume of distribution at steady state of Plasminogen
    End point type
    Secondary
    End point timeframe
    First dose and 12 weeks
    End point values
    		 Plasminogen (Human) Intravenous
    Number of subjects analysed
    15
    Units: mL/kg
    arithmetic mean (standard deviation)
        Mean (SD) Vss of plasminogen after first dose
    63.3 ± 11.44
        Mean (SD) Vss of plasminogen at Week 12
    49.3 ± 10.36
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety was assessed during the treatment period (up to 124 weeks) and a 30-day post-treatment period
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study drug treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Plasminogen (Human) Intravenous
    Reporting group description
    		 6.6 mg/kg Plasminogen (Human) Intravenous given every 2 to 4 days by a 10- to 30- minute intravenous infusion

    Serious adverse events
    		 Plasminogen (Human) Intravenous
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 15 (20.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Surgical and medical procedures
    Ear operation
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ossiculoplasty
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Plasminogen (Human) Intravenous
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 15 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cholesteatoma
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Skin papilloma
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Flushing
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Orthostatic hypotension
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Haemorrhage
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    6
    Surgical and medical procedures
    Artificial crown procedure
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Venipuncture
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Central venous catheter removal
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Tooth repair
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Wisdom teeth removal
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    3
    Chest discomfort
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Chills
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Feeling abnormal
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    4
    Influenza like illness
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Infusion site erythema
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Infusion site discomfort
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Infusion site bruising
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Infusion site rash
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Infusion site pain
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    5
    Infusion site extravasation
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    11
    Infusion site swelling
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    11
    Pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Peripheral swelling
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    6
    Pyrexia
         subjects affected / exposed
    6 / 15 (40.00%)
         occurrences all number
    13
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    3
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Ovulation pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    4
    Uterine pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pelvic pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Vulvovaginal pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Vaginal haemorrhage
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 15 (46.67%)
         occurrences all number
    7
    Diaphragmatic disorder
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    4
    Dysphonia
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    3
    Nasal oedema
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Nasal discomfort
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Nasal congestion
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    6
    Haemoptysis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    4
    Oropharyngeal discomfort
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    8 / 15 (53.33%)
         occurrences all number
    9
    Paranasal sinus discomfort
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    6 / 15 (40.00%)
         occurrences all number
    7
    Sinus congestion
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Sputum increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Throat irritation
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    6
    Mood altered
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    3
    Panic attack
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Restlessness
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blood iron decreased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blood pressure systolic increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Platelet count decreased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Progesterone decreased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Arthropod sting
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Contusion
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Joint injury
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Procedural pain
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Chest injury
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Procedural vomiting
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Road traffic accident
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Scratch
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Skin abrasion
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    4
    Tongue injury
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Wound
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    3
    Procedural nausea
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Congenital, familial and genetic disorders
    Ehlers-Danlos syndrome
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Cardiac disorders
    Cardiac flutter
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    4
    Dysgeusia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    8 / 15 (53.33%)
         occurrences all number
    37
    Migraine
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    4
    Paraesthesia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Post-traumatic headache
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Lymph node pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Lymphadenopathy
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hypoacusis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Excessive cerumen production
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Ear pain
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Motion sickness
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Tinnitus
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Tympanic membrane perforation
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Eye disorders
    Conjunctival deposit
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Eye discharge
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Eye inflammation
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Eye irritation
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Eye pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    7
    Eye swelling
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Ocular hyperaemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Abdominal pain lower
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    8
    Abdominal distension
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Abdominal pain
         subjects affected / exposed
    5 / 15 (33.33%)
         occurrences all number
    13
    Abdominal pain upper
         subjects affected / exposed
    6 / 15 (40.00%)
         occurrences all number
    14
    Aphthous ulcer
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Colitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Crohn's disease
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Dental caries
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    7 / 15 (46.67%)
         occurrences all number
    9
    Dry mouth
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Gastric dilatation
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    6
    Flatulence
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Haematochezia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Gingival bleeding
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    6 / 15 (40.00%)
         occurrences all number
    12
    Mouth ulceration
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hypoaesthesia oral
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Paraesthesia oral
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Proctalgia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Tooth development disorder
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    7
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Erythema
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Dermatitis contact
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Rash erythematous
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    6
    Pruritus
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Swelling face
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Skin exfoliation
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Tumour pruritus
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Haematuria
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Micturition urgency
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Renal pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    3
    Urinary tract pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    6
    Back pain
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    6
    Flank pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Joint swelling
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Limb discomfort
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    4
    Pain in extremity
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    7
    Myalgia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Cystitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Ear infection
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    7
    Fungal infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    3
    Hordeolum
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    H1N1 influenza
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    4
    Nasopharyngitis
         subjects affected / exposed
    10 / 15 (66.67%)
         occurrences all number
    17
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    9
    Tonsillitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Tooth infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    5
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Apr 2016
    - Change to PK sampling time at 96 hours post-dose for PK profile - Option of every fourth day dosing interval, according to the PK profile - Peak expiratory flow (PEF) added as an indicator of lung functionality tests - A definition of primary endpoint success added - Description of CGI scale updated - Description of the quality-of-life scale updated Additional administrative corrections and clarifications.
    13 Jun 2016
    - Added 1 primary and 1 secondary objective - Modified the secondary edpoint to reflect 48 weeks of duration - Added 3 subjects to the total number of subjects in order to increase the number of subjects with potentially measureable or visible lesions - Added a specified duration of treatment for Segment 3 in Norway and clarified that only subjects in the US will receive at home administration of IMP - Added a maximum dose adjustment algorithm in the event that a subject does not have a complete clinical response - Change made to allow for flexibility in the selection of the clinical specialty laboratory and added retention samples for plasminogen activity and antigen levels to allow for repeat testing if requested - Added retention samples for plasminogen antibodies to allow for repeat testing if requested - Added graded evaluation of clinical responses to provide additional details to the efficacy analysis Additional administrative clarifications and corrections.
    03 Nov 2016
    - Remove US specific wording to allow subjects in Norway to receive at home administration of IMP during Segment 3 - The duration window of the Plasminogen IV infusion was expanded to 10 to 30 minutes based on the actual experience of the subjects - The results of the Phase 1 study were updated to reflect the current findings from the study - Visit windows extended for Segment 3 visits and added for Safety Follow-up, 30 days post final dose, to allow flexibility in scheduling visits - The requirement for chest X-ray at Week 12 was revised to “at the investigator’s discretion” as this test was only relevant for subjects who had lesions with respiratory involvement Additional administrative clarifications and corrections.
    19 Dec 2016
    - The requirement for chest X-ray at baseline was revised to “at the investigator’s discretion” as this test was only relevant for subjects who had lesions with respiratory involvement - Added that Clinical Global Impression and Quality of life assessment will be performed at the Week 48 Visit only in Segment 3 Additional administrative clarifications and corrections.
    08 Aug 2018
    - IMP vial concentration has been revised from 5.0 mg/mL to 5.5 mg/mL to reflect the true concentration and dosing - Subject dosing was revised from 6.0 mg/kg to 6.6 mg/kg of plasminogen to reflect the true concentration and dosing - Due to delay in market approval, subjects at the United States site will be given the option to enroll in Treatment Protocol 2002C018G without interrupting treatment - Clinical experience with Plasminogen has been revised to include most recent data - Revision was implemented to add an End of Study visit for Subjects at the US Site Only who decide to enter Treatment Protocol 2002C018G and related assessments -Subjects’ infusions window for both Segment 2 and Segment 3 has been specified as +/- 1 day per Addendum dated 28Apr2017 - No backup sample for Plasminogen activity and antigen/antibody testing is needed at the End of Study visit for subjects who decide to enter the treatment protocol - Text updated to indicate that subjects will return the diary at the End of Study visit or Safety Follow-Up visit - Plasminogen administration procedures were updated per Addendum dated 24May2017. In June 2017, Prometic Biotherapeutics started using the 5 μM B.Braun disk filters instead of the MINSART 1.2 μM Syringe Filters Additional administrative clarifications and corrections.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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