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    Clinical Trial Results:
    Prospective, open-label, single arm, multicenter, pharmacokinetic, and safety study of a single dose intravenous human plasma-derived C1 Esterase Inhibitor (C1-INH) concentrate in patients with congenital C1-INH deficiency and hereditary angioedema

    Summary
    EudraCT number
    		 2019-001693-28
    Trial protocol
    		 DE  
    Global end of trial date
    17 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Feb 2022
    First version publication date
    17 Feb 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CONE-01
    Additional study identifiers
    ISRCTN number
    		 ISRCTN36746902
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Octapharma Pharmazeutika Produktionsges.m.b.H.
    Sponsor organisation address
    Oberlaaer Strasse 235, Vienna, Austria, 1100
    Public contact
    Global Clinical Project Manager, Octapharma Pharmazeutika Produktionsges.m.b.H., +43 (0)1 610 320, christiane.thomasser@octapharma.com
    Scientific contact
    Global Clinical Project Manager, Octapharma Pharmazeutika Produktionsges.m.b.H., +43 (0)1 610 320, christiane.thomasser@octapharma.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 Sep 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess the pharmacokinetic (PK) characteristics of OCTA-C1-INH after a single intravenous (IV) administration in HAE patients who are not experiencing an HAE attack.
    Protection of trial subjects
    This trial was conducted in accordance to the principles of ICH- GCP, ensuring that the rights, safety and well-being of patients are protected and in consistency with the Declaration of Helsinki and national regulatory requirements. Inclusion and exclusion criteria were carefully defined in order to protect subjects from contraindications, interactions with other medication and risk factors associated with the investigational medicinal product. Throughout the study safety was assessed, such as monitoring of adverse events and concomitant medication.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Sep 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belarus: 2
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Ukraine: 7
    Worldwide total number of subjects
    20
    EEA total number of subjects
    0
    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)
    0
    Adults (18-64 years)
    19
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients with documented congenital C1-INH deficiency and hereditary angioedema type I and type II were screened according to predefined in- and exclusion criteria.

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

    Arms
    Arm title
    		 OCTA-C1-INH
    Arm description
    		 The IP was given as a single dose of 20 IU/kg BW administered by slow IV injection during mandatory hospitalization.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OCTA-C1-INH
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The IP was to be reconstituted with a 2.5 mL WFI syringe by using a vial adapter and transferring the WFI into the vial containing the concentrate and was given as a single dose of 20 IU/kg BW administered by slow IV injection during mandatory hospitalization.

    Number of subjects in period 1
    		OCTA-C1-INH
    Started
    20
    Completed
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 20 20
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 38.5 (18 to 66) -
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 9 9

    End points

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    End points reporting groups
    Reporting group title
    OCTA-C1-INH
    Reporting group description
    		 The IP was given as a single dose of 20 IU/kg BW administered by slow IV injection during mandatory hospitalization.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set (FAS) is defined according to the intention-to-treat (ITT) principle and consists of all patients of the safety analysis set who satisfy all eligibility criteria and for whom any post‐baseline data is available; it is the set of eligible patients with treatment effects measured.

    Subject analysis set title
    Preinjection
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Preinjection

    Subject analysis set title
    0 minutes
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    0 minutes

    Subject analysis set title
    15 minutes
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    15 minutes

    Subject analysis set title
    1 hour
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    1 hour

    Subject analysis set title
    2 hours
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    2 hours

    Subject analysis set title
    6 hours
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    6 hours

    Subject analysis set title
    12 hours
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    12 hours

    Subject analysis set title
    24 hours
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    24 hours

    Subject analysis set title
    48 hours
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    48 hours

    Subject analysis set title
    72 hours
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    72 hours

    Subject analysis set title
    120 hours
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    120 hours

    Subject analysis set title
    144 hours
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    144 hours

    Subject analysis set title
    168 hours
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    168 hours

    Primary: C1-INH Activity concentrations

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    End point title
    		 C1-INH Activity concentrations [1]
    End point description
    Blood concentrations of C1-INH at each sampling time (Preinjection, 0 minutes, 15 minutes, 1 hour, 2 hours, 6 hours, 12 hours,24 hours, 48 hours, 72 hours, 120 hours, 144 hours, 168 hours)
    End point type
    Primary
    End point timeframe
    Preinjection, 0 minutes, 15 minutes, 1 hour, 2 hours, 6 hours, 12 hours,24 hours, 48 hours, 72 hours, 120 hours, 144 hours, 168 hours
    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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided.
    End point values
    		 Preinjection 0 minutes 15 minutes 1 hour 2 hours 6 hours 12 hours 24 hours 48 hours 72 hours 120 hours 144 hours 168 hours
    Number of subjects analysed
    17
    17
    20
    20
    20
    20
    20
    20
    20
    20
    20
    20
    20
    Units: IU/mL
    number (not applicable)
        Mean
    0.0841
    1.09
    0.826
    0.8
    0.765
    0.682
    0.637
    0.603
    0.453
    0.35
    0.142
    0.127
    0.053
        SD
    0.168
    1.1
    0.215
    0.184
    0.156
    0.116
    0.13
    0.118
    0.106
    0.0772
    0.137
    0.136
    0.109
        Median
    0
    0.73
    0.76
    0.765
    0.745
    0.67
    0.59
    0.605
    0.44
    0.335
    0.2
    0.1
    0
        Min
    0
    0.35
    0.58
    0.57
    0.55
    0.47
    0.45
    0.38
    0.22
    0.24
    0
    0
    0
        Max
    0.51
    5.2
    1.53
    1.29
    1.21
    0.88
    0.88
    0.85
    0.73
    0.52
    0.33
    0.36
    0.3
        (n)
    17
    17
    20
    20
    20
    20
    20
    20
    20
    20
    20
    20
    20
    No statistical analyses for this end point

    Primary: C1-INH Activity AUC inf

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    End point title
    		 C1-INH Activity AUC inf [2]
    End point description
    Area under the concentration-time curve from time zero extrapolated to infinite time
    End point type
    Primary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    Notes
    [2] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided.
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    1
    Units: h*IU/mL
    number (not applicable)
        Mean
    102
        Median
    102
        Min
    102
        Max
    102
        Geometric mean
    102
        (n)
    1
    No statistical analyses for this end point

    Primary: C1-INH Activity AUCnorm

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    End point title
    		 C1-INH Activity AUCnorm [3]
    End point description
    Area under the concentration-time curve normalized by the dose
    End point type
    Primary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided.
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    1
    Units: h*IU/mL/IU
    number (not applicable)
        Mean
    0.055
        Median
    0.055
        Min
    0.055
        Max
    0.055
        Geometric mean
    0.055
        (n)
    1
    No statistical analyses for this end point

    Primary: C1-INH Activity AUC last

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    End point title
    		 C1-INH Activity AUC last [4]
    End point description
    Area under the concentration-time curve from time 0 to the time of the last measurable concentration
    End point type
    Primary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided.
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    20
    Units: h*IU/mL
    number (not applicable)
        Mean
    51.6
        SD
    17.9
        Median
    49.7
        Min
    25.6
        Max
    83.9
        Geometric mean
    48.6
        Geometric mean CV (%)
    36.7
        (n)
    20
    No statistical analyses for this end point

    Primary: C1-INH Activity CL

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    End point title
    		 C1-INH Activity CL [5]
    End point description
    Clearance
    End point type
    Primary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    Notes
    [5] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided.
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    1
    Units: L/h
    number (not applicable)
        Mean
    0.0182
        Median
    0.0182
        Min
    0.0182
        Max
    0.0182
        Geometric mean
    0.0182
        (n)
    1
    No statistical analyses for this end point

    Primary: C1-INH Activity Cmax

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    End point title
    		 C1-INH Activity Cmax [6]
    End point description
    Maximum observed blood concentration
    End point type
    Primary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    Notes
    [6] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided.
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    20
    Units: IU/mL
    number (not applicable)
        Mean
    1.14
        SD
    0.989
        Median
    0.85
        Min
    0.85
        Max
    5.2
        Geometric mean
    0.973
        Geometric mean CV (%)
    49.8
        (n)
    20
    No statistical analyses for this end point

    Primary: C1-INH Activity Cmax/D

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    End point title
    		 C1-INH Activity Cmax/D [7]
    End point description
    Maximum observed blood concentration normalized by the dose
    End point type
    Primary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    Notes
    [7] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided.
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    20
    Units: IU/mL/IU
    number (not applicable)
        Mean
    0.00083
        SD
    0.000841
        Median
    0.000664
        Min
    0.000353
        Max
    0.00433
        Geometric mean
    0.000687
        Geometric mean CV (%)
    54.7
        (n)
    20
    No statistical analyses for this end point

    Primary: C1-INH Activity T 1/2

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    End point title
    		 C1-INH Activity T 1/2 [8]
    End point description
    Elimination half-life
    End point type
    Primary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    Notes
    [8] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided.
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    20
    Units: (h)
    number (not applicable)
        Mean
    74.1
        SD
    19
        Median
    77.2
        Min
    39.5
        Max
    109
        Geometric mean
    71.6
        Geometric mean CV (%)
    28.1
        (n)
    20
    No statistical analyses for this end point

    Primary: C1-INH Activity MRT

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    End point title
    		 C1-INH Activity MRT [9]
    End point description
    Mean residence time
    End point type
    Primary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    Notes
    [9] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided.
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    1
    Units: (h)
    number (not applicable)
        Mean
    85.5
        Median
    85.5
        Min
    85.5
        Max
    85.5
        Geometric mean
    85.5
        (n)
    1
    No statistical analyses for this end point

    Primary: C1-INH Activity Tmax

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    End point title
    		 C1-INH Activity Tmax [10]
    End point description
    Time to maximum blood concentration
    End point type
    Primary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    Notes
    [10] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided.
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    20
    Units: (h)
    number (not applicable)
        Mean
    0.598
        SD
    0.716
        Median
    0.308
        Min
    0.0667
        Max
    2.08
        Geometric mean
    0.295
        Geometric mean CV (%)
    189
        (n)
    20
    No statistical analyses for this end point

    Primary: C1-INH Activity Vd

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    End point title
    		 C1-INH Activity Vd [11]
    End point description
    Volume of distribution
    End point type
    Primary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    Notes
    [11] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided.
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    1
    Units: (L)
    number (not applicable)
        Mean
    1.52
        Median
    1.52
        Min
    1.52
        Max
    1.52
        Geometric mean
    1.52
        (n)
    1
    No statistical analyses for this end point

    Primary: C1-INH Activity IR

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    End point title
    		 C1-INH Activity IR [12]
    End point description
    Incremental recovery
    End point type
    Primary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    Notes
    [12] - 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: The system does not permit reporting of statistical analyses for studies with only 1 arm/reporting group. Therefore, only results for this endpoint are provided.
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    20
    Units: ([IU*kg]/[IU*mL])
    number (not applicable)
        Mean
    0.0466
        SD
    0.051
        Median
    0.0388
        Min
    -0.0065
        Max
    0.246
        Geometric mean
    0.0367
        Geometric mean CV (%)
    91.4
        (n)
    20
    No statistical analyses for this end point

    Secondary: C1-INH Antigen Concentrations

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    End point title
    		 C1-INH Antigen Concentrations
    End point description
    Blood concentrations of C1-INH antigen at each sampling time (Preinjection, 0 minutes, 15 minutes, 1 hour, 2 hours, 6 hours, 12 hours,24 hours, 48 hours, 72 hours, 120 hours, 144 hours, 168 hours)
    End point type
    Secondary
    End point timeframe
    Preinjection, 0 minutes, 15 minutes, 1 hour, 2 hours, 6 hours, 12 hours,24 hours, 48 hours, 72 hours, 120 hours, 144 hours, 168 hours
    End point values
    		 Preinjection 0 minutes 15 minutes 1 hour 2 hours 6 hours 12 hours 24 hours 48 hours 72 hours 120 hours 144 hours 168 hours
    Number of subjects analysed
    17
    16
    20
    20
    20
    20
    20
    20
    20
    20
    20
    20
    20
    Units: g/L
    number (not applicable)
        Mean
    0.1
    0.216
    0.211
    0.201
    0.192
    0.195
    0.179
    0.167
    0.142
    0.126
    0.093
    0.0865
    0.085
        SD
    0.107
    0.105
    0.0961
    0.102
    0.0822
    0.0816
    0.0797
    0.085
    0.0766
    0.0815
    0.088
    0.0921
    0.0919
        Median
    0.05
    0.18
    0.19
    0.17
    0.165
    0.18
    0.155
    0.14
    0.12
    0.1
    0.07
    0.06
    0.06
        Min
    0
    0.12
    0.12
    0.09
    0.1
    0.1
    0.1
    0.11
    0.09
    0.08
    0.02
    0
    0.03
        Max
    0.37
    0.51
    0.54
    0.51
    0.47
    0.48
    0.47
    0.46
    0.41
    0.4
    0.41
    0.42
    0.43
        (n)
    17
    16
    20
    20
    20
    20
    20
    20
    20
    20
    20
    20
    20
    No statistical analyses for this end point

    Secondary: C1-INH Antigen AUCinf

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    End point title
    		 C1-INH Antigen AUCinf
    End point description
    Area under the concentration-time curve from time zero extrapolated to infinite time
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    2
    Units: h*g/L
    number (not applicable)
        Mean
    17.8
        SD
    0.871
        Median
    17.8
        Min
    17.1
        Max
    18.4
        Geometric mean
    17.8
        Geometric mean CV (%)
    4.91
        (n)
    2
    No statistical analyses for this end point

    Secondary: C1-INH Antigen AUCnorm

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    End point title
    		 C1-INH Antigen AUCnorm
    End point description
    Area under the concentration-time curve normalized by the dose
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    2
    Units: h*g/L/g
    number (not applicable)
        Mean
    46.7
        SD
    6.82
        Median
    46.7
        Min
    41.9
        Max
    51.5
        Geometric mean
    46.4
        Geometric mean CV (%)
    14.7
        (n)
    2
    No statistical analyses for this end point

    Secondary: C1-INH Antigen AUClast

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    End point title
    		 C1-INH Antigen AUClast
    End point description
    Area under the concentration-time curve from time 0 to the time of the last measurable concentration
    End point type
    Secondary
    End point timeframe
    Timeframe: Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    20
    Units: h*g/L/g
    number (not applicable)
        Mean
    20.7
        SD
    14
        Median
    16.2
        Min
    13.8
        Max
    71.5
        Geometric mean
    18.5
        Geometric mean CV (%)
    43.4
        (n)
    20
    No statistical analyses for this end point

    Secondary: C1-INH Antigen CL

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    End point title
    		 C1-INH Antigen CL
    End point description
    Clearance
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    2
    Units: L/h
    number (not applicable)
        Mean
    0.0216
        SD
    0.00316
        Median
    0.0216
        Min
    0.0194
        Max
    0.0239
        Geometric mean
    0.0215
        Geometric mean CV (%)
    14.7
        (n)
    2
    No statistical analyses for this end point

    Secondary: C1-INH Antigen Cmax

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    End point title
    		 C1-INH Antigen Cmax
    End point description
    Maximum observed blood concentration
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    20
    Units: g/L
    number (not applicable)
        Mean
    0.239
        SD
    0.1
        Median
    0.205
        Min
    0.15
        Max
    0.54
        Geometric mean
    0.224
        Geometric mean CV (%)
    35.4
        (n)
    20
    No statistical analyses for this end point

    Secondary: C1-INH Antigen Cmax/D

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    End point title
    		 C1-INH Antigen Cmax/D
    End point description
    Maximum observed blood concentration normalized by the dose
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    20
    Units: g/L/g
    number (not applicable)
        Mean
    0.718
        SD
    0.368
        Median
    0.655
        Min
    0.341
        Max
    1.78
        Geometric mean
    0.655
        Geometric mean CV (%)
    43
        (n)
    20
    No statistical analyses for this end point

    Secondary: C1-INH Antigen T1/2

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    End point title
    		 C1-INH Antigen T1/2
    End point description
    Elimination half-life
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    19
    Units: (h)
    number (not applicable)
        Mean
    118
        SD
    76.4
        Median
    104
        Min
    46.9
        Max
    416
        Geometric mean
    106
        Geometric mean CV (%)
    46.1
        (n)
    19
    No statistical analyses for this end point

    Secondary: C1-INH Antigen MRT

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    End point title
    		 C1-INH Antigen MRT
    End point description
    Mean residence time
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    2
    Units: (h)
    number (not applicable)
        Mean
    78.5
        SD
    12.8
        Median
    78.5
        Min
    69.4
        Max
    87.5
        Geometric mean
    78
        Geometric mean CV (%)
    16.4
        (n)
    2
    No statistical analyses for this end point

    Secondary: C1-INH Antigen Tmax

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    End point title
    		 C1-INH Antigen Tmax
    End point description
    Time to maximum blood concentration
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    20
    Units: (h)
    number (not applicable)
        Mean
    1.54
        SD
    2.38
        Median
    0.317
        Min
    0
        Max
    6.1
        Geometric mean
    0.453
        Geometric mean CV (%)
    420
        (n)
    20
    No statistical analyses for this end point

    Secondary: C1-INH Antigen Vd

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    End point title
    		 C1-INH Antigen Vd
    End point description
    Volume of distribution
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    2
    Units: (L)
    number (not applicable)
        Mean
    1.57
        SD
    0.0674
        Median
    1.57
        Min
    1.52
        Max
    1.61
        Geometric mean
    1.57
        Geometric mean CV (%)
    4.31
        (n)
    2
    No statistical analyses for this end point

    Secondary: C4 Antigen Concentrations

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    End point title
    		 C4 Antigen Concentrations
    End point description
    Blood concentrations of C4 Antigen at each sampling time (Preinjection, 0 minutes, 15 minutes, 1 hour, 2 hours, 6 hours, 12 hours,24 hours, 48 hours, 72 hours, 120 hours, 144 hours, 168 hours)
    End point type
    Secondary
    End point timeframe
    Preinjection, 0 minutes, 15 minutes, 1 hour, 2 hours, 6 hours, 12 hours,24 hours, 48 hours, 72 hours, 120 hours, 144 hours, 168 hours
    End point values
    		 Preinjection 0 minutes 15 minutes 1 hour 2 hours 6 hours 12 hours 24 hours 48 hours 72 hours 120 hours 144 hours 168 hours
    Number of subjects analysed
    17
    17
    20
    20
    20
    20
    20
    20
    20
    20
    20
    20
    20
    Units: g/L
    number (not applicable)
        Mean
    0.0482
    0.04
    0.0425
    0.0465
    0.049
    0.073
    0.0765
    0.087
    0.11
    0.115
    0.0945
    0.082
    0.072
        SD
    0.0238
    0.0203
    0.0234
    0.027
    0.0288
    0.0305
    0.0248
    0.0292
    0.0361
    0.0444
    0.0389
    0.0405
    0.0409
        Median
    0.05
    0.04
    0.04
    0.04
    0.05
    0.07
    0.08
    0.09
    0.105
    0.11
    0.09
    0.08
    0.07
        Min
    0.02
    0.01
    0.01
    0.02
    0
    0.03
    0.03
    0.04
    0.06
    0.06
    0.01
    0.01
    0.02
        Max
    0.11
    0.1
    0.1
    0.11
    0.1
    0.13
    0.13
    0.18
    0.22
    0.27
    0.21
    0.21
    0.21
        (n)
    17
    17
    20
    20
    20
    20
    20
    20
    20
    20
    20
    20
    20
    No statistical analyses for this end point

    Secondary: C4 Antigen AUCinf

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    End point title
    		 C4 Antigen AUCinf
    End point description
    Area under the concentration-time curve from time zero extrapolated to infinite time
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    2
    Units: h*g/L
    number (not applicable)
        Mean
    13.4
        SD
    5.9
        Median
    13.4
        Min
    9.25
        Max
    17.6
        Geometric mean
    12.8
        Geometric mean CV (%)
    47.9
        (n)
    2
    No statistical analyses for this end point

    Secondary: C4 Antigen AUClast

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    End point title
    		 C4 Antigen AUClast
    End point description
    Area under the concentration-time curve from time 0 to the time of the last measurable concentration
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    20
    Units: h*g/L
    number (not applicable)
        Mean
    15.8
        SD
    4.68
        Median
    15.7
        Min
    8.37
        Max
    28.4
        Geometric mean
    15.1
        Geometric mean CV (%)
    30.9
        (n)
    20
    No statistical analyses for this end point

    Secondary: C4 Antigen Cmax

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    End point title
    		 C4 Antigen Cmax
    End point description
    Maximum observed blood concentration
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    20
    Units: g/L
    number (not applicable)
        Mean
    0.129
        SD
    0.0467
        Median
    0.125
        Min
    0.07
        Max
    0.27
        Geometric mean
    0.122
        Geometric mean CV (%)
    33.1
        (n)
    20
    No statistical analyses for this end point

    Secondary: C4 Antigen T1/2

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    End point title
    		 C4 Antigen T1/2
    End point description
    Elimination half-life
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    13
    Units: (h)
    number (not applicable)
        Mean
    85.4
        SD
    34.8
        Median
    82.6
        Min
    27.5
        Max
    134
        Geometric mean
    77.3
        Geometric mean CV (%)
    53.7
        (n)
    13
    No statistical analyses for this end point

    Secondary: C4 Antigen MRT

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    End point title
    		 C4 Antigen MRT
    End point description
    Mean residence time
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    2
    Units: (h)
    number (not applicable)
        Mean
    89.7
        SD
    3.91
        Median
    89.7
        Min
    86.9
        Max
    92.4
        Geometric mean
    89.6
        Geometric mean CV (%)
    4.37
        (n)
    2
    No statistical analyses for this end point

    Secondary: C4 Antigen Tmax

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    End point title
    		 C4 Antigen Tmax
    End point description
    Time to maximum blood concentration
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 7 after IMP injection
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    20
    Units: (h)
    number (not applicable)
        Mean
    53.7
        SD
    22.8
        Median
    59.4
        Min
    6
        Max
    72.7
        Geometric mean
    44.3
        Geometric mean CV (%)
    93.8
        (n)
    20
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the whole study from V1 (screeening) up to final visit (Visit 9 or early discontinuation).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Safety analysis (SA) set
    Reporting group description
    		 The safety analysis (SA) set consists of all patients who receive any amount of the IMP injection.

    Serious adverse events
    		 Safety analysis (SA) set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Safety analysis (SA) set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 20 (35.00%)
    Investigations
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Congenital, familial and genetic disorders
    Hereditary angioedema
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Psychiatric disorders
    Mixed anxiety and depressive disorder
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Osteoporosis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Nov 2019
    Protocol V03 + Amendment V01: Implementation of German competent authority (PEI) comments in their letter of deficiency dated 07-Nov-2019 to initial study submission: • one additional PK at timepoint 2 hours after IMP administration • Wells probability score for DVT and PE at 3 timepoints and subsequent D-dimer testing and where required a Doppler screening for DVT • include Adverse Events of Special Interest (AESI) of thromboembolic event (TEE) type as standalone safety endpoint
    30 Jan 2020
    Protocol V02.2 (Submitted in UKR only ): • Implementation of Ukrainian competent authority comments in their Letter of deficiency dated 22 Nov 2019 to initial study submission. Development phase was re-classified to “phase 1” • Mandatory hospitalization for patient observation during and after IMP administration (24 hours from Day 0 to Day 1).
    29 Apr 2020
    Protocol V04 + Amendment V03: • Implementation of Ukrainian competent authority comments to include mandatory hospitalization for 24 hours. • Serology testing was added for more precise testing.
    03 May 2020
    Protocol V04.1 (Submitted in UKR only) • Implementation of German competent authority comments (PEI): - one additional PK at timepoint 2 hours after IMP administration - Wells probability score for DVT and PE at 3 timepoints and subsequent D-dimer testing and where required a Doppler screening for DVT - including Adverse Events of Special Interest (AESI) of thromboembolic event (TEE) type as standalone safety endpoint • Serology testing was added for more precise testing.
    30 Dec 2020
    Protocol V05.1 (Submitted in UKR only): • Adaption of exclusion criterion #5 to exclude also female patients on specific androgen therapy.
    30 Dec 2020
    Protocol V05 + Amendment V04: • Adaption of exclusion criterion #5 to exclude also female patients on specific androgen therapy

    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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