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    Clinical Trial Results:
    Safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple subcutaneous doses of NNC0365-3769 (Mim8) in healthy subjects and in subjects with haemophilia A with or without factor VIII inhibitors

    Summary
    EudraCT number
    		 2019-000465-20
    Trial protocol
    		 DE   GB   ES   AT   BG   PL   IT  
    Global end of trial date
    06 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Apr 2024
    First version publication date
    21 Apr 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    NN7769-4513
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04204408
    WHO universal trial number (UTN)
    		 U1111-1227-4220
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Office (2834), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Office (2834), Novo Nordisk A/S, clinicaltrials@novonordisk.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
    09 Feb 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the safety and tolerability of subcutaneous Mim8 in healthy subjects and in subjects with severe haemophilia A with or without FVIII inhibitors
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2013) and International Council for Harmonisation (ICH) Good Clinical Practice, including archiving of essential documents (2016), and 21 Code of Federal Regulations (CFR) 312.120.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jan 2020
    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
    Germany: 48
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Japan: 2
    Country: Number of subjects enrolled
    Poland: 12
    Country: Number of subjects enrolled
    South Africa: 3
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Türkiye: 5
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    100
    EEA total number of subjects
    74
    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)
    0
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    94
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 SAD part was conducted at one site in Germany. MAD part was conducted at 18 sites in 11 countries: (Austria, Bulgaria, Italy, Japan, South Africa, Switzerland, United Kingdom)-1, Poland-2, Spain-2, Turkey-3 and United States-4. EXP was conducted at 9 sites in 6 countries: (Italy, Spain, Switzerland, United Kingdom)-1, Poland-2 and United States-3.

    Pre-assignment
    Screening details
    		 The trial had phase 1 SAD part and phase 2 MAD part, conducted in an overlapping fashion. MAD phase had a main and extension period. After completing 12-week treatment in the main period, subjects continued treatment for up to 148 weeks in the extension period. The trial also included an exploratory biomarker cohort of emicizumab-treated subjects.

    Period 1
    Period 1 title
    overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Single ascending dose (SAD) cohort 1
    Arm description
    		 Subjects received a single dose of 0.6 milligrams (mg) Mim8 (NNC0365-3769) subcutaneously.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NNC0365-3769 A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received a single dose of 0.6 milligrams (mg) Mim8 (NNC0365-3769) subcutaneously.

    Arm title
    		 SAD cohort 2
    Arm description
    		 Subjects received a single dose of 3 milligrams (mg) Mim8 subcutaneously.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NNC0365-3769 A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received a single dose of 3 milligrams (mg) Mim8 subcutaneously.

    Arm title
    		 SAD cohort 3
    Arm description
    		 Subjects received a single dose of 12 milligrams (mg) Mim8 subcutaneously.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NNC0365-3769 A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received a single dose of 12 milligrams (mg) Mim8 subcutaneously.

    Arm title
    		 SAD cohort 4
    Arm description
    		 Subjects received a single dose of 24 milligrams (mg) Mim8 subcutaneously.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NNC0365-3769 A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received a single dose of 24 milligrams (mg) Mim8 subcutaneously.

    Arm title
    		 SAD cohort 5
    Arm description
    		 Subjects received a single dose of 29 milligrams (mg) Mim8 subcutaneously.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NNC0365-3769 A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received a single dose of 29 milligrams (mg) Mim8 subcutaneously.

    Arm title
    		 SAD cohort 6
    Arm description
    		 Subjects received a single dose of 48 milligrams (mg) Mim8 subcutaneously.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NNC0365-3769 A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received a single dose of 48 milligrams (mg) Mim8 subcutaneously.

    Arm title
    		 SAD placebo
    Arm description
    		 Subjects received a single dose of placebo matched with Mim8 subcutaneously.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received a single dose of placebo matched with Mim8 subcutaneously.

    Arm title
    		 Multiple ascending dose (MAD) cohort 1
    Arm description
    		 Subjects received 1.0/1.2 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NNC0365-3769 A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 1.0/1.2 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Arm title
    		 MAD cohort 2
    Arm description
    		 Subjects received 2.4/3.8 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NNC0365-3769 A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 2.4/3.8 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Arm title
    		 MAD cohort 3
    Arm description
    		 Subjects received 11.0/15.0 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NNC0365-3769 A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 11.0/15.0 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Arm title
    		 MAD cohort 4
    Arm description
    		 Subjects received 41.0/60.0 milligrams (mg) dose of Mim8 subcutaneously once monthly for 12-weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NNC0365-3769 A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 41.0/60.0 milligrams (mg) dose of Mim8 subcutaneously once monthly for 12-weeks.

    Arm title
    		 MAD cohort 5
    Arm description
    		 Subjects received 24.0/35.0 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NNC0365-3769 A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 24.0/35.0 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Arm title
    		 Exploratory biomarker cohort: Naive
    Arm description
    		 Subjects received emicizumab in accordance with standard of care of the prescribed product.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Emicizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received emicizumab in accordance with standard of care of the prescribed product.

    Arm title
    		 Exploratory biomarker cohort: Non-Naive
    Arm description
    		 Subjects received emicizumab in accordance with standard of care of the prescribed product.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Emicizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received emicizumab in accordance with standard of care of the prescribed product.

    Number of subjects in period 1
    		Single ascending dose (SAD) cohort 1 SAD cohort 2 SAD cohort 3 SAD cohort 4 SAD cohort 5 SAD cohort 6 SAD placebo Multiple ascending dose (MAD) cohort 1 MAD cohort 2 MAD cohort 3 MAD cohort 4 MAD cohort 5 Exploratory biomarker cohort: Naive Exploratory biomarker cohort: Non-Naive
    Started
    6
    6
    6
    6
    6
    6
    12
    7
    9
    8
    8
    10
    7
    3
    Full analysis set (FAS)
    6
    6
    6
    6
    6
    6
    12
    7
    9
    8
    8
    10
    7
    3
    Safety analysis set (SAS)
    6
    6
    6
    6
    6
    6
    12
    7
    9
    8
    8
    10
    7
    3
    Completed
    5
    5
    6
    6
    6
    5
    12
    7
    8
    8
    8
    10
    6
    3
    Not completed
    1
    1
    0
    0
    0
    1
    0
    0
    1
    0
    0
    0
    1
    0
         Consent withdrawn by subject
    1
    1
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    -
    -
    -
    -
    -
    -
    1
    -
    -
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    -
    -
    1
    -
    -
    -
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Single ascending dose (SAD) cohort 1
    Reporting group description
    		 Subjects received a single dose of 0.6 milligrams (mg) Mim8 (NNC0365-3769) subcutaneously.

    Reporting group title
    SAD cohort 2
    Reporting group description
    		 Subjects received a single dose of 3 milligrams (mg) Mim8 subcutaneously.

    Reporting group title
    SAD cohort 3
    Reporting group description
    		 Subjects received a single dose of 12 milligrams (mg) Mim8 subcutaneously.

    Reporting group title
    SAD cohort 4
    Reporting group description
    		 Subjects received a single dose of 24 milligrams (mg) Mim8 subcutaneously.

    Reporting group title
    SAD cohort 5
    Reporting group description
    		 Subjects received a single dose of 29 milligrams (mg) Mim8 subcutaneously.

    Reporting group title
    SAD cohort 6
    Reporting group description
    		 Subjects received a single dose of 48 milligrams (mg) Mim8 subcutaneously.

    Reporting group title
    SAD placebo
    Reporting group description
    		 Subjects received a single dose of placebo matched with Mim8 subcutaneously.

    Reporting group title
    Multiple ascending dose (MAD) cohort 1
    Reporting group description
    		 Subjects received 1.0/1.2 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Reporting group title
    MAD cohort 2
    Reporting group description
    		 Subjects received 2.4/3.8 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Reporting group title
    MAD cohort 3
    Reporting group description
    		 Subjects received 11.0/15.0 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Reporting group title
    MAD cohort 4
    Reporting group description
    		 Subjects received 41.0/60.0 milligrams (mg) dose of Mim8 subcutaneously once monthly for 12-weeks.

    Reporting group title
    MAD cohort 5
    Reporting group description
    		 Subjects received 24.0/35.0 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Reporting group title
    Exploratory biomarker cohort: Naive
    Reporting group description
    		 Subjects received emicizumab in accordance with standard of care of the prescribed product.

    Reporting group title
    Exploratory biomarker cohort: Non-Naive
    Reporting group description
    		 Subjects received emicizumab in accordance with standard of care of the prescribed product.

    Reporting group values
    		 Single ascending dose (SAD) cohort 1 SAD cohort 2 SAD cohort 3 SAD cohort 4 SAD cohort 5 SAD cohort 6 SAD placebo Multiple ascending dose (MAD) cohort 1 MAD cohort 2 MAD cohort 3 MAD cohort 4 MAD cohort 5 Exploratory biomarker cohort: Naive Exploratory biomarker cohort: Non-Naive Total
    Number of subjects
    		 6 6 6 6 6 6 12 7 9 8 8 10 7 3 100
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 1 2 1 2 0 0 0 6
        Adults (18-64 years)
    		 6 6 6 6 6 6 12 6 7 7 6 10 7 3 94
        From 65-84 years
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.7 ( 7.8 ) 30.7 ( 4.4 ) 35.3 ( 5.8 ) 28.8 ( 7.6 ) 32.5 ( 8.2 ) 28.0 ( 5.7 ) 27.5 ( 6.2 ) 30.3 ( 10.1 ) 35.8 ( 17.0 ) 32.8 ( 11.4 ) 32.3 ( 15.3 ) 36.7 ( 13.2 ) 29.7 ( 8.3 ) 34.7 ( 4.5 ) -
    Gender Categorical
    Units: Subjects
        Male
    		 6 6 6 6 6 6 12 7 9 8 8 10 7 3 100

    End points

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    End points reporting groups
    Reporting group title
    Single ascending dose (SAD) cohort 1
    Reporting group description
    		 Subjects received a single dose of 0.6 milligrams (mg) Mim8 (NNC0365-3769) subcutaneously.

    Reporting group title
    SAD cohort 2
    Reporting group description
    		 Subjects received a single dose of 3 milligrams (mg) Mim8 subcutaneously.

    Reporting group title
    SAD cohort 3
    Reporting group description
    		 Subjects received a single dose of 12 milligrams (mg) Mim8 subcutaneously.

    Reporting group title
    SAD cohort 4
    Reporting group description
    		 Subjects received a single dose of 24 milligrams (mg) Mim8 subcutaneously.

    Reporting group title
    SAD cohort 5
    Reporting group description
    		 Subjects received a single dose of 29 milligrams (mg) Mim8 subcutaneously.

    Reporting group title
    SAD cohort 6
    Reporting group description
    		 Subjects received a single dose of 48 milligrams (mg) Mim8 subcutaneously.

    Reporting group title
    SAD placebo
    Reporting group description
    		 Subjects received a single dose of placebo matched with Mim8 subcutaneously.

    Reporting group title
    Multiple ascending dose (MAD) cohort 1
    Reporting group description
    		 Subjects received 1.0/1.2 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Reporting group title
    MAD cohort 2
    Reporting group description
    		 Subjects received 2.4/3.8 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Reporting group title
    MAD cohort 3
    Reporting group description
    		 Subjects received 11.0/15.0 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Reporting group title
    MAD cohort 4
    Reporting group description
    		 Subjects received 41.0/60.0 milligrams (mg) dose of Mim8 subcutaneously once monthly for 12-weeks.

    Reporting group title
    MAD cohort 5
    Reporting group description
    		 Subjects received 24.0/35.0 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Reporting group title
    Exploratory biomarker cohort: Naive
    Reporting group description
    		 Subjects received emicizumab in accordance with standard of care of the prescribed product.

    Reporting group title
    Exploratory biomarker cohort: Non-Naive
    Reporting group description
    		 Subjects received emicizumab in accordance with standard of care of the prescribed product.

    Subject analysis set title
    MAD Extension Cohort 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a 1.0/1.2 milligrams (mg) of Mim8 subcutaneously once weekly for 148 weeks after 12-weeks treatment period (up to 160 weeks in total).

    Subject analysis set title
    MAD Extension Cohort 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a 2.4/3.8 milligrams (mg) of Mim8 subcutaneously once weekly for 148 weeks after 12-weeks treatment period (up to 160 weeks in total).

    Subject analysis set title
    MAD Extension Cohort 3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a 11.0/15.0 milligrams (mg) of Mim8 subcutaneously once weekly for 148 weeks after 12-weeks treatment period (up to 160 weeks in total).

    Subject analysis set title
    MAD Extension Cohort 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a 41.0/60.0 milligrams (mg) of Mim8 subcutaneously once monthly for 148 weeks after 12-weeks treatment period (up to 160 weeks in total).

    Subject analysis set title
    MAD Extension Cohort 5
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a 24.0/35.0 milligrams (mg) of Mim8 subcutaneously once weekly for 148 weeks after 12-weeks treatment period (up to 160 weeks in total).

    Subject analysis set title
    MAD Extension Maintenance (QW)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a 6.0/11.0 milligrams (mg) of Mim8 subcutaneously once weekly for 148 weeks after 12-weeks treatment period (up to 160 weeks in total).

    Subject analysis set title
    MAD Extension Maintenance (QM)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a 30.0/46.0 milligrams (mg) of Mim8 subcutaneously once monthly for 148 weeks after 12-weeks treatment period (up to 160 weeks in total).

    Primary: Single ascending dose (SAD) part: Number of treatment emergent adverse events

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    End point title
    		 Single ascending dose (SAD) part: Number of treatment emergent adverse events [1] [2]
    End point description
    Number of treatment emergent adverse events from time of dosing (Day 1) to Week 16 is presented. An adverse event (AE) is any untoward medical occurrence in a clinical trial subject that is temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Treatment emergent adverse events (TEAEs) were defined as AEs occurring after the first trial product administration and until week 16. The SAS included all subjects exposed to the trial product.
    End point type
    Primary
    End point timeframe
    From time of dosing (Day 1) to Week 16
    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: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Single ascending dose (SAD) cohort 1 SAD cohort 2 SAD cohort 3 SAD cohort 4 SAD cohort 5 SAD cohort 6 SAD placebo
    Number of subjects analysed
    6
    6
    6
    6
    6
    6
    12
    Units: Events
        number (not applicable)
    8
    9
    7
    11
    6
    14
    24
    No statistical analyses for this end point

    Primary: Extensíon to the MAD part: Number of treatment emergent adverse events

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    End point title
    		 Extensíon to the MAD part: Number of treatment emergent adverse events [3]
    End point description
    Number of treatment emergent adverse events from Week 12 up to Week 176 (16 weeks after last dose) is presented. An adverse event (AE) is any untoward medical occurrence in a clinical trial subject that is temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Treatment emergent adverse events (TEAEs) were defined as AEs occurring after the first trial product administration and until 16 weeks after the last dose. The SAS included all subjects exposed to the trial product.
    End point type
    Primary
    End point timeframe
    From Week 12 up to Week 176 (16 weeks after last dose)
    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: As per the end point the data were provided for safety analysis and so no statistical analysis was specified.
    End point values
    		 MAD Extension Cohort 1 MAD Extension Cohort 2 MAD Extension Cohort 3 MAD Extension Cohort 4 MAD Extension Cohort 5 MAD Extension Maintenance (QW) MAD Extension Maintenance (QM)
    Number of subjects analysed
    6
    13
    11
    8
    10
    31
    9
    Units: Events
        number (not applicable)
    6
    36
    31
    19
    16
    56
    10
    No statistical analyses for this end point

    Primary: Multiple ascending dose (MAD) part: Number of treatment emergent adverse events

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    End point title
    		 Multiple ascending dose (MAD) part: Number of treatment emergent adverse events [4] [5]
    End point description
    Number of treatment emergent adverse events from time of dosing (Day 1) to Week 12 is presented. An adverse event (AE) is any untoward medical occurrence in a clinical trial subject that is temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Treatment emergent adverse events (TEAEs) were defined as AEs occurring after the first trial product administration and until 16 weeks after the last dose. The SAS included all subjects exposed to the trial product.
    End point type
    Primary
    End point timeframe
    From time of first dosing (day 1) to week 12
    Notes
    [4] - 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: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Multiple ascending dose (MAD) cohort 1 MAD cohort 2 MAD cohort 3 MAD cohort 4 MAD cohort 5
    Number of subjects analysed
    7
    9
    8
    8
    10
    Units: Events
    1
    12
    10
    8
    10
    No statistical analyses for this end point

    Secondary: Single ascending dose (SAD) part: Number of injection site reactions

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    End point title
    		 Single ascending dose (SAD) part: Number of injection site reactions [6]
    End point description
    Number of injection site reactions from time of dosing (day 1) to week 16 is presented. The SAS included all subjects exposed to the trial product.
    End point type
    Secondary
    End point timeframe
    From time of dosing (day 1) to week 16
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Single ascending dose (SAD) cohort 1 SAD cohort 2 SAD cohort 3 SAD cohort 4 SAD cohort 5 SAD cohort 6
    Number of subjects analysed
    6
    6
    6
    6
    6
    6
    Units: Events
        number (not applicable)
    0
    1
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Single ascending dose (SAD) part: Relative change in D-dimer

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    End point title
    		 Single ascending dose (SAD) part: Relative change in D-dimer [7]
    End point description
    Relative change in D-dimer (measured in nanograms per milliliter (ng/mL)) from baseline (day 1) to week 16 is presented. The SAS included all subjects exposed to the trial product. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline (day 1) to week 16
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Single ascending dose (SAD) cohort 1 SAD cohort 2 SAD cohort 3 SAD cohort 4 SAD cohort 5 SAD cohort 6 SAD placebo
    Number of subjects analysed
    5
    5
    6
    6
    6
    5
    12
    Units: Percentage change in D-dimer
        number (not applicable)
    16.09
    84.51
    68.49
    1.30
    40.09
    31.43
    30.62
    No statistical analyses for this end point

    Secondary: Single ascending dose (SAD) part: Relative change in prothrombin fragment 1 and 2

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    End point title
    		 Single ascending dose (SAD) part: Relative change in prothrombin fragment 1 and 2 [8]
    End point description
    Relative change in prothrombin fragment 1 and 2 (measured in picomoles per liter (pmol/L)) from baseline (day 1) to week 16 is presented. The SAS included all subjects exposed to the trial product. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline (day 1) to week 16
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Single ascending dose (SAD) cohort 1 SAD cohort 2 SAD cohort 3 SAD cohort 4 SAD cohort 5 SAD cohort 6 SAD placebo
    Number of subjects analysed
    5
    5
    6
    6
    6
    5
    12
    Units: Percentage change in prothrombin
        number (not applicable)
    50.67
    89.14
    18.48
    4.13
    30.39
    61.55
    35.20
    No statistical analyses for this end point

    Secondary: Single ascending dose (SAD) part: Relative change in fibrinogen

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    End point title
    		 Single ascending dose (SAD) part: Relative change in fibrinogen [9]
    End point description
    Relative change in fibrinogen (measured in gram per liter (g/L)) from baseline (day 1) to week 16 is presented. The SAS included all subjects exposed to the trial product. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline (day 1) to week 16
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Single ascending dose (SAD) cohort 1 SAD cohort 2 SAD cohort 3 SAD cohort 4 SAD cohort 5 SAD cohort 6 SAD placebo
    Number of subjects analysed
    5
    5
    6
    6
    6
    5
    12
    Units: Percentage change in fibrinogen
        number (not applicable)
    -11.77
    28.56
    14.16
    -12.78
    -9.32
    -8.08
    0.92
    No statistical analyses for this end point

    Secondary: Single ascending dose (SAD) part: Relative change in platelets

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    End point title
    		 Single ascending dose (SAD) part: Relative change in platelets [10]
    End point description
    Relative change in platelets (measured in 10^9 per liter (10^9/L)) from baseline (day 1) to week 16 is presented. The SAS included all subjects exposed to the trial product. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline (day 1) to week 16
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Single ascending dose (SAD) cohort 1 SAD cohort 2 SAD cohort 3 SAD cohort 4 SAD cohort 5 SAD cohort 6 SAD placebo
    Number of subjects analysed
    5
    5
    6
    6
    6
    5
    12
    Units: Percentage change in platelets
        number (not applicable)
    -3.46
    7.52
    12.14
    -4.48
    1.39
    2.84
    -2.14
    No statistical analyses for this end point

    Secondary: Single ascending dose (SAD) part: Cmax, SD: the maximum concentration of Mim8 after a single dose

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    End point title
    		 Single ascending dose (SAD) part: Cmax, SD: the maximum concentration of Mim8 after a single dose [11]
    End point description
    Maximum concentration of Mim8 after a single dose from baseline (day 1) to week 16 is presented. The FAS included all subjects with at least one valid pharmacokinetics (PK) or pharmacodynamics (PD) assessment. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline (day 1) to week 16
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Single ascending dose (SAD) cohort 1 SAD cohort 2 SAD cohort 3 SAD cohort 4 SAD cohort 5 SAD cohort 6
    Number of subjects analysed
    5
    5
    6
    6
    6
    5
    Units: Micrograms per milliliter (μg/mL)
        arithmetic mean (standard deviation)
    0.060 ( 0.013 )
    0.316 ( 0.071 )
    0.769 ( 0.143 )
    1.432 ( 0.360 )
    2.803 ( 0.497 )
    3.544 ( 0.840 )
    No statistical analyses for this end point

    Secondary: Single ascending dose (SAD) part: t1/2, SD: the terminal half-life of Mim8 after a single dose

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    End point title
    		 Single ascending dose (SAD) part: t1/2, SD: the terminal half-life of Mim8 after a single dose [12]
    End point description
    Terminal half-life of Mim8 after a single dose from baseline (day 1) to week 16 is presented. The FAS included all subjects with at least one valid PK or PD assessment. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline (day 1) to week 16
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Single ascending dose (SAD) cohort 1 SAD cohort 2 SAD cohort 3 SAD cohort 4 SAD cohort 5 SAD cohort 6
    Number of subjects analysed
    5
    5
    6
    6
    6
    5
    Units: Days
        arithmetic mean (standard deviation)
    26.901 ( 3.143 )
    32.944 ( 3.343 )
    30.857 ( 4.508 )
    32.062 ( 4.504 )
    30.332 ( 2.624 )
    31.323 ( 6.406 )
    No statistical analyses for this end point

    Secondary: Single ascending dose (SAD) part: AUC0-inf, SD: the area under the Mim8 concentration-time curve from time 0 to infinity after a single dose

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    End point title
    		 Single ascending dose (SAD) part: AUC0-inf, SD: the area under the Mim8 concentration-time curve from time 0 to infinity after a single dose [13]
    End point description
    Area under the Mim8 concentration-time curve from time 0 to infinity after a single dose from baseline (day 1) to week 16 is presented. The FAS included all subjects with at least one valid PK or PD assessment. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline (day 1) to week 16
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Single ascending dose (SAD) cohort 1 SAD cohort 2 SAD cohort 3 SAD cohort 4 SAD cohort 5 SAD cohort 6
    Number of subjects analysed
    5
    5
    6
    6
    6
    5
    Units: Microgram*day per milliliter (μg*day/mL)
        arithmetic mean (standard deviation)
    3.011 ( 0.436 )
    17.649 ( 4.574 )
    42.051 ( 11.702 )
    81.518 ( 27.892 )
    135.189 ( 18.163 )
    194.439 ( 67.607 )
    No statistical analyses for this end point

    Secondary: Single ascending dose (SAD) part: Change in activated partial thromboplastin time

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    End point title
    		 Single ascending dose (SAD) part: Change in activated partial thromboplastin time [14]
    End point description
    Change in activated partial thromboplastin time from baseline (day 1) to week 16 is presented. The Activated Partial Thromboplastin Time (aPTT) assay records the time for clot formation. It includes both the time for activation of FVIII and the time for FVIIIa to support FIXa activity and thereby facilitate clotting. It measures the number of seconds it takes for a clot to form in a sample of blood after substances (reagents) are added. The FAS included all subjects with at least one valid PK or PD assessment. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline (day 1) to week 16
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Single ascending dose (SAD) cohort 1 SAD cohort 2 SAD cohort 3 SAD cohort 4 SAD cohort 5 SAD cohort 6 SAD placebo
    Number of subjects analysed
    5
    5
    6
    6
    6
    5
    12
    Units: Seconds
        arithmetic mean (standard deviation)
    75.2 ( 9.4 )
    53.8 ( 6.5 )
    48.2 ( 3.9 )
    38.8 ( 5.2 )
    37.7 ( 3.8 )
    37.0 ( 2.8 )
    95.8 ( 11.4 )
    No statistical analyses for this end point

    Secondary: Single ascending dose (SAD) part: tmax, SD: the time to maximum concentration of Mim8 after a single dose

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    End point title
    		 Single ascending dose (SAD) part: tmax, SD: the time to maximum concentration of Mim8 after a single dose [15]
    End point description
    Time to maximum concentration of Mim8 after a single dose from baseline (day 1) to week 16 is presented. The FAS included all subjects with at least one valid PK or PD assessment. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline (day 1) to week 16
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Single ascending dose (SAD) cohort 1 SAD cohort 2 SAD cohort 3 SAD cohort 4 SAD cohort 5 SAD cohort 6
    Number of subjects analysed
    5
    5
    6
    6
    6
    5
    Units: Days
        arithmetic mean (standard deviation)
    9.993 ( 2.535 )
    8.594 ( 4.137 )
    11.662 ( 1.493 )
    8.653 ( 3.982 )
    8.992 ( 1.073 )
    11.979 ( 1.439 )
    No statistical analyses for this end point

    Secondary: MAD part (weekly and monthly dosing): Number of injection site reactions

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    End point title
    		 MAD part (weekly and monthly dosing): Number of injection site reactions [16]
    End point description
    Number of injection site reactions from time of first dosing (day 1) to week 12 is presented. The SAS included all subjects exposed to the trial product.
    End point type
    Secondary
    End point timeframe
    From time of first dosing (day 1) to week 12
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Multiple ascending dose (MAD) cohort 1 MAD cohort 2 MAD cohort 3 MAD cohort 4 MAD cohort 5
    Number of subjects analysed
    7
    9
    8
    8
    10
    Units: Events
        number (not applicable)
    0
    2
    1
    0
    1
    No statistical analyses for this end point

    Secondary: MAD part (weekly and monthly dosing): Relative change in D-dimer

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    End point title
    		 MAD part (weekly and monthly dosing): Relative change in D-dimer [17]
    End point description
    Relative change in D-dimer (measured in milligrams per liter (mg/L)) from baseline (day 1) to week 12 is presented. The SAS included all subjects exposed to the trial product. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline (day 1) to week 12
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Multiple ascending dose (MAD) cohort 1 MAD cohort 2 MAD cohort 3 MAD cohort 4 MAD cohort 5
    Number of subjects analysed
    7
    7
    8
    8
    10
    Units: Percentage change in D-dimer
        number (not applicable)
    12.23
    27.16
    2.48
    18.17
    9.81
    No statistical analyses for this end point

    Secondary: MAD part (weekly and monthly dosing): Occurrence of anti-Mim8 antibodies

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    End point title
    		 MAD part (weekly and monthly dosing): Occurrence of anti-Mim8 antibodies [18]
    End point description
    Number of subjects with occurrence of anti-Mim8 antibodies from baseline (day 1) to week 12 is presented. The SAS included all subjects exposed to the trial product.
    End point type
    Secondary
    End point timeframe
    From baseline (day 1) to week 12
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Multiple ascending dose (MAD) cohort 1 MAD cohort 2 MAD cohort 3 MAD cohort 4 MAD cohort 5
    Number of subjects analysed
    7
    9
    8
    8
    10
    Units: Subjects
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: MAD part (weekly and monthly dosing): Relative change in fibrinogen

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    End point title
    		 MAD part (weekly and monthly dosing): Relative change in fibrinogen [19]
    End point description
    Relative change in fibrinogen (measured in gram per liter (g/L)) from baseline (day 1) to week 12 is presented. The SAS included all subjects exposed to the trial product. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline (day 1) to week 12
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Multiple ascending dose (MAD) cohort 1 MAD cohort 2 MAD cohort 3 MAD cohort 4 MAD cohort 5
    Number of subjects analysed
    7
    7
    8
    8
    10
    Units: Percentage change in fibrinogen
        number (not applicable)
    3.80
    -4.95
    -16.63
    -12.41
    -14.24
    No statistical analyses for this end point

    Secondary: MAD part (weekly and monthly dosing): Relative change in prothrombin fragment 1 and 2

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    End point title
    		 MAD part (weekly and monthly dosing): Relative change in prothrombin fragment 1 and 2 [20]
    End point description
    Relative change in prothrombin fragment 1 and 2 (measured in picomoles per liter (pmol/L)) from baseline (day 1) to week 12 is presented. The SAS included all subjects exposed to the trial product. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline (day 1) to week 12
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Multiple ascending dose (MAD) cohort 1 MAD cohort 2 MAD cohort 3 MAD cohort 4 MAD cohort 5
    Number of subjects analysed
    7
    7
    8
    8
    10
    Units: Percentage change in prothrombin
        number (not applicable)
    26.08
    93.99
    323.65
    606.41
    310.25
    No statistical analyses for this end point

    Secondary: MAD part (weekly and monthly dosing): Relative change in platelets

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    End point title
    		 MAD part (weekly and monthly dosing): Relative change in platelets [21]
    End point description
    Relative change in platelets (measured in 10^9 per liter (10^9/L)) from baseline (day 1) to week 12 is presented. The SAS included all subjects exposed to the trial product. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline (day 1) to week 12
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Multiple ascending dose (MAD) cohort 1 MAD cohort 2 MAD cohort 3 MAD cohort 4 MAD cohort 5
    Number of subjects analysed
    7
    7
    8
    8
    10
    Units: Percentage change in platelets
        number (not applicable)
    2.01
    -2.62
    2.24
    2.91
    5.77
    No statistical analyses for this end point

    Secondary: MAD part, PK session 2 (weekly dosing): Cmax, MD: the maximum concentration of Mim8 after multiple doses

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    End point title
    		 MAD part, PK session 2 (weekly dosing): Cmax, MD: the maximum concentration of Mim8 after multiple doses [22]
    End point description
    Maximum concentration of Mim8 after multiple doses from day 57 to day 64 is presented. The FAS included all subjects with at least one valid PK or PD assessment.
    End point type
    Secondary
    End point timeframe
    From day 57 to day 64
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Multiple ascending dose (MAD) cohort 1 MAD cohort 2 MAD cohort 3 MAD cohort 5
    Number of subjects analysed
    7
    9
    8
    10
    Units: Micrograms per milliliter (μg/mL)
        arithmetic mean (standard deviation)
    1.025 ( 0.264 )
    3.077 ( 0.722 )
    9.328 ( 2.833 )
    18.369 ( 6.506 )
    No statistical analyses for this end point

    Secondary: MAD part, PK session 2 (weekly dosing): AUCτ, MD: the area under the Mim8 concentration-time curve in the dosing interval after multiple doses

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    End point title
    		 MAD part, PK session 2 (weekly dosing): AUCτ, MD: the area under the Mim8 concentration-time curve in the dosing interval after multiple doses [23]
    End point description
    Area under the Mim8 concentration-time curve in the dosing interval after multiple doses from day 57 to day 64 is presented. The FAS included all subjects with at least one valid PK or PD assessment.
    End point type
    Secondary
    End point timeframe
    From day 57 to day 64
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Multiple ascending dose (MAD) cohort 1 MAD cohort 2 MAD cohort 3 MAD cohort 5
    Number of subjects analysed
    7
    9
    8
    10
    Units: Microgram*day per milliliter (μg*day/mL)
        arithmetic mean (standard deviation)
    6.641 ( 1.431 )
    19.339 ( 3.822 )
    58.285 ( 17.772 )
    115.490 ( 38.824 )
    No statistical analyses for this end point

    Secondary: MAD part, PK session 2 (monthly dosing): Cmax, MD: the maximum concentration of Mim8 after multiple doses

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    End point title
    		 MAD part, PK session 2 (monthly dosing): Cmax, MD: the maximum concentration of Mim8 after multiple doses [24]
    End point description
    Maximum concentration of Mim8 after multiple doses from day 57 to day 85 is presented. The FAS included all subjects with at least one valid PK or PD assessment. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From day 57 to day 85
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 MAD cohort 4
    Number of subjects analysed
    7
    Units: Micrograms per milliliter (μg/mL)
        arithmetic mean (standard deviation)
    10.226 ( 2.118 )
    No statistical analyses for this end point

    Secondary: MAD part (weekly dosing): Mean of maximum thrombin generation (peak height)

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    End point title
    		 MAD part (weekly dosing): Mean of maximum thrombin generation (peak height) [25]
    End point description
    Mean of maximum thrombin generation (peak height) from day 57 to day 64 is presented. Thrombin peak height reflects the haemostatic potential as the maximum amount of thrombin produced during the thrombin generation assay. The FAS included all subjects with at least one valid PK or PD assessment. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From day 57 to day 64
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 Multiple ascending dose (MAD) cohort 1 MAD cohort 2 MAD cohort 3 MAD cohort 5
    Number of subjects analysed
    6
    9
    7
    10
    Units: Nanometer (nM)
        arithmetic mean (standard deviation)
    106.61 ( 23.50 )
    150.95 ( 33.18 )
    188.47 ( 26.51 )
    208.35 ( 25.23 )
    No statistical analyses for this end point

    Secondary: MAD part, PK session 2 (monthly dosing): AUCτ, MD: the area under the Mim8 concentration-time curve in the dosing interval after multiple doses

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    End point title
    		 MAD part, PK session 2 (monthly dosing): AUCτ, MD: the area under the Mim8 concentration-time curve in the dosing interval after multiple doses [26]
    End point description
    Area under the Mim8 concentration-time curve in the dosing interval after multiple doses from day 57 to day 85 is presented. The FAS included all subjects with at least one valid PK or PD assessment. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From day 57 to day 85
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 MAD cohort 4
    Number of subjects analysed
    7
    Units: Microgram*day per milliliter (μg*day/mL)
        arithmetic mean (standard deviation)
    230.934 ( 49.723 )
    No statistical analyses for this end point

    Secondary: MAD part (monthly dosing): Mean of maximum thrombin generation (peak height)

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    End point title
    		 MAD part (monthly dosing): Mean of maximum thrombin generation (peak height) [27]
    End point description
    Mean of maximum thrombin generation (peak height) from day 57 to day 85 is presented. Thrombin peak height reflects the haemostatic potential as the maximum amount of thrombin produced during the thrombin generation assay. The FAS included all subjects with at least one valid PK or PD assessment. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From day 57 to day 85
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all the arms were evaluated for this end point. Data is provided for the arms evaluated for this end point.
    End point values
    		 MAD cohort 4
    Number of subjects analysed
    6
    Units: Nanometer (nM)
        arithmetic mean (standard deviation)
    204.22 ( 45.67 )
    No statistical analyses for this end point

    Secondary: Extension to the MAD part: Number of injection site reactions

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    End point title
    		 Extension to the MAD part: Number of injection site reactions
    End point description
    Number of injection site reactions from week 12 up to week 176 is presented. The SAS included all subjects exposed to the trial product.
    End point type
    Secondary
    End point timeframe
    From week 12 up to week 176
    End point values
    		 MAD Extension Cohort 1 MAD Extension Cohort 2 MAD Extension Cohort 3 MAD Extension Cohort 4 MAD Extension Cohort 5 MAD Extension Maintenance (QW) MAD Extension Maintenance (QM)
    Number of subjects analysed
    6
    13
    11
    8
    10
    31
    9
    Units: Events
        number (not applicable)
    1
    2
    2
    0
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Extension to the MAD part: Occurrence of anti-Mim8 antibodies

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    End point title
    		 Extension to the MAD part: Occurrence of anti-Mim8 antibodies
    End point description
    Number of subjects with occurrence of anti-Mim8 antibodies from week 12 up to week 176 is presented. The SAS included all subjects exposed to the trial product.
    End point type
    Secondary
    End point timeframe
    From week 12 up to week 176
    End point values
    		 MAD Extension Cohort 1 MAD Extension Cohort 2 MAD Extension Cohort 3 MAD Extension Cohort 4 MAD Extension Cohort 5 MAD Extension Maintenance (QW) MAD Extension Maintenance (QM)
    Number of subjects analysed
    6
    13
    11
    8
    10
    31
    9
    Units: Subjects
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Single ascending dose (SAD): From time of dosing (Day 1) to Week 16 Multiple ascending dose (MAD): From time of first dosing (day 1) to week 12 Multiple ascending dose (MAD) extensíon: From Week 12 up to Week 176 (16 weeks after last dose)
    Adverse event reporting additional description
    All presented AEs are treatment emergent. Treatment emergent adverse events (TEAEs) were defined as AEs occurring: SAD part: after the first trial product administration and until week 16. MAD part: after the first trial product administration and until 16 weeks after the last dose. Exploratory biomarker cohort: from the first to last visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26
    Reporting groups
    Reporting group title
    MAD cohort 2
    Reporting group description
    		 Subjects received 2.4/3.8 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Reporting group title
    MAD cohort 1
    Reporting group description
    		 Subjects received 1.0/1.2 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Reporting group title
    MAD cohort 5
    Reporting group description
    		 Subjects received 24.0/35.0 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Reporting group title
    SAD cohort 1
    Reporting group description
    		 Subjects received a single dose of 0.6 milligrams (mg) Mim8 (NNC0365-3769) subcutaneously.

    Reporting group title
    Emicizumab
    Reporting group description
    		 Subjects received emicizumab in accordance with standard of care of the prescribed product.

    Reporting group title
    SAD cohort 3
    Reporting group description
    		 Subjects received a single dose of 12 milligrams (mg) Mim8 subcutaneously.

    Reporting group title
    SAD cohort 4
    Reporting group description
    		 Subjects received a single dose of 24 milligrams (mg) Mim8 subcutaneously.

    Reporting group title
    SAD cohort 5
    Reporting group description
    		 Subjects received a single dose of 29 milligrams (mg) Mim8 subcutaneously.

    Reporting group title
    SAD cohort 6
    Reporting group description
    		 Subjects received a single dose of 48 milligrams (mg) Mim8 subcutaneously.

    Reporting group title
    SAD placebo
    Reporting group description
    		 Subjects received a single dose of placebo matched with Mim8 subcutaneously.

    Reporting group title
    MAD cohort 4
    Reporting group description
    		 Subjects received 41.0/60.0 milligrams (mg) dose of Mim8 subcutaneously once monthly for 12-weeks.

    Reporting group title
    MAD cohort 3
    Reporting group description
    		 Subjects received 11.0/15.0 milligrams (mg) dose of Mim8 subcutaneously once weekly for 12-weeks.

    Reporting group title
    SAD cohort 2
    Reporting group description
    		 Subjects received a single dose of 3 milligrams (mg) Mim8 subcutaneously.

    Serious adverse events
    		 MAD cohort 2 MAD cohort 1 MAD cohort 5 SAD cohort 1 Emicizumab SAD cohort 3 SAD cohort 4 SAD cohort 5 SAD cohort 6 SAD placebo MAD cohort 4 MAD cohort 3 SAD cohort 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hodgkin's disease
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MAD cohort 2 MAD cohort 1 MAD cohort 5 SAD cohort 1 Emicizumab SAD cohort 3 SAD cohort 4 SAD cohort 5 SAD cohort 6 SAD placebo MAD cohort 4 MAD cohort 3 SAD cohort 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 9 (88.89%)
    6 / 7 (85.71%)
    10 / 10 (100.00%)
    3 / 6 (50.00%)
    2 / 10 (20.00%)
    3 / 6 (50.00%)
    5 / 6 (83.33%)
    3 / 6 (50.00%)
    5 / 6 (83.33%)
    11 / 12 (91.67%)
    7 / 8 (87.50%)
    7 / 8 (87.50%)
    5 / 6 (83.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Microangiopathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Surgical and medical procedures
    Artificial crown procedure
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Tooth restoration
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    2 / 8 (25.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Chest discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Chills
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Inflammation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Injection site bruising
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Injection site erythema
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Injection site haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 7 (28.57%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Injection site haemorrhage
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Injection site induration
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Injection site pain
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Food allergy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Hypersensitivity
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Testicular pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Dry throat
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Nasal dryness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    0
    1
    0
    1
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Panic attack
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Investigations
    Antinuclear antibody positive
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Heart rate increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Protein urine present
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Prothrombin fragment 1.2 increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    2 / 8 (25.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Accidental overdose
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Arthropod bite
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Contusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Foot fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Hand fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Immunisation reaction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    0
    Incorrect route of product administration
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Incorrect dose administered
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Joint injury
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Limb injury
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Muscle strain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Road traffic accident
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Skin laceration
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    2 / 10 (20.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Spinal column injury
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Tooth fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Venomous sting
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 12 (25.00%)
    2 / 8 (25.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    1
    0
    3
    2
    2
    0
    3
    4
    2
    2
    2
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Eye disorders
    Blepharospasm
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Refraction disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Strabismus
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    1
    Dental caries
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    1
    1
    0
    0
    0
    1
    1
    Dyspepsia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    3
    0
    Erosive oesophagitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Faeces pale
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Faeces discoloured
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Food poisoning
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    1
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Hiatus hernia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Hyperchlorhydria
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Intestinal mass
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    1
    0
    1
    0
    Oesophageal motility disorder
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Swollen tongue
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Vomiting
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Gallbladder polyp
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Non-alcoholic fatty liver
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    0
    Dermatitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Eczema
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Rash erythematous
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Urticaria
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Proteinuria
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Renal colic
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Ureterolithiasis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    2 / 10 (20.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    2 / 8 (25.00%)
    3 / 8 (37.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    1
    0
    0
    0
    1
    2
    3
    0
    Bone pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Back pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    0
    Flank pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Joint noise
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Limb discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Muscle tightness
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Muscle twitching
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    2
    0
    0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Tendonitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 7 (28.57%)
    4 / 10 (40.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    3 / 8 (37.50%)
    3 / 8 (37.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    4
    0
    0
    0
    0
    0
    0
    0
    3
    3
    0
    Folliculitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    1
    Helicobacter gastritis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    3 / 6 (50.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    4 / 6 (66.67%)
    4 / 12 (33.33%)
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    3
    0
    1
    1
    1
    4
    4
    1
    2
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    2
    0
    0
    0
    0
    0
    0
    0
    1
    4
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Viral infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Hyperlipidaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Iron deficiency
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Nov 2019
    A more conservative dose escalation than originally proposed was implemented in the SAD part of the trial and a population switching criterion was added. The SAD and MAD flowcharts were updated to reflect sampling timepoints for all PD markers and it was clarified that no formal statistical tests were to be performed. Minor changes to exclusion criteria and typographical corrections were made.
    13 Mar 2020
    Sentinel dosing was implemented in the MAD part of the trial to increase subject safety and a reduction of the washout period of prophylactic – or on demand – medicine was added. Genotyping was added as part of the screening procedure in the MAD part to reduce the number of screening failures. Subjects were invited to separately consent to genotyping. For subjects not consenting to genotyping the original exclusion criterion based on factor II activity or activated protein C resistance was applied. Three other exclusion criteria were clarified to give more guidance to the investigators. Randomisation was implemented for the MAD cohorts 3 and 4 to avoid selection bias issues.
    10 Jun 2020
    An extension to the MAD part of the trial was added, which would allow long-term safety assessment of Mim8 in male adults and adolescents with haemophilia A (HA) with or without factor VIII inhibitors. Coronavirus disease of 2019 (COVID-19) mitigation strategies were also included.
    29 Oct 2020
    The dose level for the MAD cohort 4 was changed. Subjects were randomised between MAD cohorts 3 and 4 representing regimens with once-weekly and once-monthly dosing, respectively. In order to randomise the subjects to similar expected average exposure levels in the two cohorts, the dose level for once-monthly dosing was increased to align with the corresponding dose level for once-weekly dosing. The rationale was to investigate the safety of Mim8 prophylaxis at a higher comparable dose level, yet still 10-fold below the no-observed-adverse-effect level (NOAEL), between once-weekly and once-monthly administration frequencies, in male adults and adolescents with HA with and without FVIII inhibitors.
    07 May 2021
    A 6th SAD cohort and a 5th MAD cohort (once-weekly dosing regimen) were added. The 6th SAD cohort was added to collect necessary data for dose proportionality analyses. The 5th MAD cohort was added to collect data from subjects who were exposed to a higher Mim8 dose, which was needed to determine the optimal Mim8 dosing scheme for different weight ranges in future trials. The predicted exposure level from this dose remained more than 3-fold below the NOAEL. Also, the protocol was amended to allow subjects to receive approved COVID-19 vaccines, to adjust the section for replacement of subjects (ensuring sufficient data for endpoint assessment), to define that data from a minimum of 5 subjects were needed for the trial safety group to evaluate safety and to decide on ascending to the next dose level, to adjust the section for interim reporting (ensuring that safety summaries and interim analyses could be prepared at relevant time points), and to make minor corrections throughout the protocol.
    12 Oct 2021
    A switch of subjects to a new trial product formulation (Mim8 formulation B) during the MAD extension was added and the interim reporting section was amended to accommodate this formulation switch. Also, the recommended activated prothrombin complex concentrate (aPCC) treatment of bleeding episodes was aligned with that of other future Mim8 trials.
    28 Apr 2022
    The duration of the MAD extension period of the trial has been extended with 56 weeks and total number of subject visits increased. Number of doses subjects will receive if completing the entire trial duration has been increased to 40 for once-monthly dosing and up to 160 for once-weekly dosing. The maximum amount of blood to be collected in the MAD extension period has been increased due to the additional visits. Discontinuation criterion for the MAD part has been updated to include major surgery and COVID-19.

    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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