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    Clinical Trial Results:
    Factor XI LICA to Reduce Thrombotic Events in End-Stage Renal Disease Patients on Hemodialysis: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of BAY 2976217

    Summary
    EudraCT number
    2019-003927-39
    Trial protocol
    CZ   DE   LV   GR   BG   HU  
    Global end of trial date
    12 May 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    22 May 2023
    First version publication date
    22 May 2023
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    BAY2976217/21170
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04534114
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    12 May 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective was to evaluate the safety of fesomersen as compared to placebo.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 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
    Belgium: 11
    Country: Number of subjects enrolled
    Bulgaria: 21
    Country: Number of subjects enrolled
    Czechia: 14
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Greece: 23
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Japan: 32
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Latvia: 7
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Russian Federation: 88
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    Ukraine: 36
    Country: Number of subjects enrolled
    United States: 17
    Worldwide total number of subjects
    307
    EEA total number of subjects
    116
    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)
    200
    From 65 to 84 years
    102
    85 years and over
    5

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Study was conducted at 69 study centers in 15 countries between 04-SEP-2020 (first subject first visit) and 12-MAY-2022 (last subject last visit).

    Pre-assignment
    Screening details
    From 359 subjects screened, 51 subjects were screening failure and a total of 308 subjects were randomized and 307 were treated either with fesomersen or placebo.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Fesomersen 40 mg
    Arm description
    Subjects received monthly subcutaneous treatment with 40 mg fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.
    Arm type
    Experimental

    Investigational medicinal product name
    Fesomersen sodium
    Investigational medicinal product code
    BAY2976217
    Other name
    Factor XI LICA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous treatment with 40 mg fesomersen.

    Arm title
    Fesomersen 80 mg
    Arm description
    Subjects received monthly subcutaneous treatment with 80 mg fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.
    Arm type
    Experimental

    Investigational medicinal product name
    Fesomersen sodium
    Investigational medicinal product code
    BAY2976217
    Other name
    Factor XI LICA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous treatment with 80 mg fesomersen.

    Arm title
    Fesomersen 120 mg
    Arm description
    Subjects received monthly subcutaneous treatment with 120 mg fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.
    Arm type
    Experimental

    Investigational medicinal product name
    Fesomersen sodium
    Investigational medicinal product code
    BAY2976217
    Other name
    Factor XI LICA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous treatment with 120 mg fesomersen.

    Arm title
    Placebo
    Arm description
    Subjects received monthly subcutaneous treatment with matching placebo to fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.
    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
    Matching placebo.

    Number of subjects in period 1
    Fesomersen 40 mg Fesomersen 80 mg Fesomersen 120 mg Placebo
    Started
    77
    79
    76
    75
    Completed
    67
    66
    64
    61
    Not completed
    10
    13
    12
    14
         Adverse event, serious fatal
    1
    -
    -
    1
         COVID-19 pandemic: Adverse event
    -
    1
    1
    -
         Physician decision
    -
    -
    -
    1
         COVID-19 pandemic: withdrawal following protocol
    1
    3
    3
    1
         Participant decision
    1
    3
    3
    1
         COVID-19 pandemic: Death
    -
    1
    -
    2
         Adverse event, non-fatal
    4
    2
    1
    2
         Protocol-specified withdrawal criterion met
    2
    1
    4
    6
         Other reason
    1
    1
    -
    -
         COVID-19 pandemic: Participant decision
    -
    1
    -
    -
    Period 2
    Period 2 title
    Extension treatment period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Fesomersen 40 mg
    Arm description
    Subjects received monthly subcutaneous treatment with 40 mg fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.
    Arm type
    Experimental

    Investigational medicinal product name
    Fesomersen sodium
    Investigational medicinal product code
    BAY2976217
    Other name
    Factor XI LICA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous treatment with 40 mg fesomersen.

    Arm title
    Fesomersen 80 mg
    Arm description
    Subjects received monthly subcutaneous treatment with 80 mg fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.
    Arm type
    Experimental

    Investigational medicinal product name
    Fesomersen sodium
    Investigational medicinal product code
    BAY2976217
    Other name
    Factor XI LICA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous treatment with 80 mg fesomersen.

    Arm title
    Fesomersen 120 mg
    Arm description
    Subjects received monthly subcutaneous treatment with 120 mg fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.
    Arm type
    Experimental

    Investigational medicinal product name
    Fesomersen sodium
    Investigational medicinal product code
    BAY2976217
    Other name
    Factor XI LICA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous treatment with 120 mg fesomersen.

    Arm title
    Placebo
    Arm description
    Subjects received monthly subcutaneous treatment with matching placebo to fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.
    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
    Matching placebo.

    Number of subjects in period 2 [1]
    Fesomersen 40 mg Fesomersen 80 mg Fesomersen 120 mg Placebo
    Started
    62
    61
    63
    58
    Completed
    59
    57
    62
    53
    Not completed
    3
    4
    1
    5
         Adverse event, serious fatal
    -
    -
    1
    2
         COVID-19 pandemic: withdrawal following protocol
    1
    -
    -
    -
         COVID-19 pandemic: Death
    -
    -
    -
    1
         Protocol-specified withdrawal criterion met
    2
    2
    -
    1
         Adverse event, non-fatal
    -
    1
    -
    1
         Other reason
    -
    1
    -
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all subjects completed main treatment period entered extension treatment period.

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Fesomersen 40 mg
    Reporting group description
    Subjects received monthly subcutaneous treatment with 40 mg fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.

    Reporting group title
    Fesomersen 80 mg
    Reporting group description
    Subjects received monthly subcutaneous treatment with 80 mg fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.

    Reporting group title
    Fesomersen 120 mg
    Reporting group description
    Subjects received monthly subcutaneous treatment with 120 mg fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received monthly subcutaneous treatment with matching placebo to fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.

    Reporting group values
    Fesomersen 40 mg Fesomersen 80 mg Fesomersen 120 mg Placebo Total
    Number of subjects
    77 79 76 75 307
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    60.4 ± 13.2 58.0 ± 14.4 57.7 ± 13.3 58.6 ± 11.9 -
    Gender categorical
    Units: Subjects
        Female
    35 20 30 22 107
        Male
    42 59 46 53 200
    Race
    Units: Subjects
        Asian
    12 8 11 13 44
        Black or African american
    2 1 4 1 8
        Not reported
    1 0 0 0 1
        White
    62 70 61 61 254
    Ethnicity
    Units: Subjects
        Hispanic or latino
    3 6 1 2 12
        Not hispanic or latino
    74 73 75 72 294
        Not reported
    0 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Fesomersen 40 mg
    Reporting group description
    Subjects received monthly subcutaneous treatment with 40 mg fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.

    Reporting group title
    Fesomersen 80 mg
    Reporting group description
    Subjects received monthly subcutaneous treatment with 80 mg fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.

    Reporting group title
    Fesomersen 120 mg
    Reporting group description
    Subjects received monthly subcutaneous treatment with 120 mg fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received monthly subcutaneous treatment with matching placebo to fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.
    Reporting group title
    Fesomersen 40 mg
    Reporting group description
    Subjects received monthly subcutaneous treatment with 40 mg fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.

    Reporting group title
    Fesomersen 80 mg
    Reporting group description
    Subjects received monthly subcutaneous treatment with 80 mg fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.

    Reporting group title
    Fesomersen 120 mg
    Reporting group description
    Subjects received monthly subcutaneous treatment with 120 mg fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received monthly subcutaneous treatment with matching placebo to fesomersen (Factor XI LICA). LICA=Ligand conjugated antisense oligonucleotide.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Safety analysis set (SAF) includes all randomized subjects who received at least one dose of the study intervention according to actual treatment arm received.

    Subject analysis set title
    Pharmacokinetic analysis set (PKS)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Pharmacokinetic analysis set (PKS) includes all fesomersen-treated subjects with at least 1 PK sample in accordance with the PK sampling schedule and without deviation from the protocol that would interfere with the evaluation of the PK data were included in the PK analysis.

    Subject analysis set title
    Pharmacodynamic set (PDS)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Pharmacodynamic set (PDS) includes all subjects with at least 1 PD sample in accordance with the PD sampling schedule and without deviation from the protocol that would interfere with the evaluation of the PD data were included in the PD analysis.

    Primary: Incidence of composite of major bleeding (MB) and clinically-relevant non-major bleeding (CRNMB) during the main treatment period and within the on-treatment time window, as assessed by blinded central independent adjudication committee (CIAC)

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    End point title
    Incidence of composite of major bleeding (MB) and clinically-relevant non-major bleeding (CRNMB) during the main treatment period and within the on-treatment time window, as assessed by blinded central independent adjudication committee (CIAC)
    End point description
    MB is defined as symptomatic bleeding and: 1) Fatal bleeding, and/or; 2) Bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, and/or; 3) Bleeding causing a fall in hemoglobin level of 20 g/L (2.0 g/dL) (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or red cells. CRNMB is defined as any sign or symptom of hemorrhage that does not fit the criteria for the ISTH definition of major bleeding but does meet at least one of the following criteria: 1) Requiring medical intervention by a healthcare professional; 2) Leading to hospitalization or increased level of care; 3) Prompting a face-to-face evaluation. n/100 person-years: number of subjects with incident events divided by the cumulative at-risk time in the reference population, where a subject is no longer at risk once an incident event occurred.
    End point type
    Primary
    End point timeframe
    Up to 24 weeks
    End point values
    Fesomersen 40 mg Fesomersen 80 mg Fesomersen 120 mg Placebo
    Number of subjects analysed
    77 [1]
    79 [2]
    76 [3]
    75 [4]
    Units: n/100 person-years
        number (confidence interval 95%)
    9.0 (2.5 to 18.9)
    9.1 (2.5 to 19.1)
    6.1 (1.1 to 14.5)
    9.7 (2.7 to 20.4)
    Notes
    [1] - SAF
    [2] - SAF
    [3] - SAF
    [4] - SAF
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Fesomersen groups were compared to the placebo group using two-sided log-rank tests. Due to the exploratory nature of these analyses, no multiplicity adjustment was done. Cause-specific hazard ratio and corresponding 2-sided 95% confidence intervals, comparing the hazards for the event-of-interest in each of the Fesomersen groups with the placebo group were estimated based on three separate cause-specific Cox proportional hazards models as exploratory analysis.
    Comparison groups
    Fesomersen 40 mg v Placebo
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.944
    Method
    Logrank
    Parameter type
    Cause specific Hazard ratio
    Point estimate
    0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.19
         upper limit
    4.68
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Fesomersen groups were compared to the placebo group using two-sided log-rank tests. Due to the exploratory nature of these analyses, no multiplicity adjustment was done. Cause-specific hazard ratio and corresponding 2-sided 95% confidence intervals, comparing the hazards for the event-of-interest in each of the Fesomersen groups with the placebo group were estimated based on three separate cause-specific Cox proportional hazards models as exploratory analysis.
    Comparison groups
    Fesomersen 80 mg v Placebo
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.953
    Method
    Logrank
    Parameter type
    Cause specific Hazard ratio
    Point estimate
    0.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.19
         upper limit
    4.72
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Fesomersen groups were compared to the placebo group using two-sided log-rank tests. Due to the exploratory nature of these analyses, no multiplicity adjustment was done. Cause-specific hazard ratio and corresponding 2-sided 95% confidence intervals, comparing the hazards for the event-of-interest in each of the Fesomersen groups with the placebo group were estimated based on three separate cause-specific Cox proportional hazards models as exploratory analysis.
    Comparison groups
    Fesomersen 120 mg v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.605
    Method
    Logrank
    Parameter type
    Cause specific Hazard ratio
    Point estimate
    0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1
         upper limit
    3.75

    Secondary: Incidence of composite of MB and CRNMB during the main and extended treatment periods and within the on-treatment time window, as assessed by blinded CIAC

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    End point title
    Incidence of composite of MB and CRNMB during the main and extended treatment periods and within the on-treatment time window, as assessed by blinded CIAC
    End point description
    MB is defined as symptomatic bleeding and: 1) Fatal bleeding, and/or; 2) Bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, and/or; 3) Bleeding causing a fall in hemoglobin level of 20 g/L (2.0 g/dL) (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or red cells. CRNMB is defined as any sign or symptom of hemorrhage that does not fit the criteria for the ISTH definition of major bleeding but does meet at least one of the following criteria: 1) Requiring medical intervention by a healthcare professional; 2) Leading to hospitalization or increased level of care; 3) Prompting a face-to-face evaluation. n/100 person-years: number of subjects with incident events divided by the cumulative at-risk time in the reference population, where a subject is no longer at risk once an incident event occurred.
    End point type
    Secondary
    End point timeframe
    Up to 48 weeks
    End point values
    Fesomersen 40 mg Fesomersen 80 mg Fesomersen 120 mg Placebo
    Number of subjects analysed
    77 [5]
    79 [6]
    76 [7]
    75 [8]
    Units: n/100 person-years
        number (confidence interval 95%)
    10.7 (4.2 to 19.7)
    8.6 (2.9 to 16.7)
    6.4 (1.7 to 13.3)
    7.0 (1.9 to 14.8)
    Notes
    [5] - SAF
    [6] - SAF
    [7] - SAF
    [8] - SAF
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Fesomersen groups were compared to the placebo group using two-sided log-rank tests. Due to the exploratory nature of these analyses, no multiplicity adjustment was done. Cause-specific hazard ratio and corresponding 2-sided 95% confidence intervals, comparing the hazards for the event-of-interest in each of the Fesomersen groups with the placebo group were estimated based on three separate cause-specific Cox proportional hazards models as exploratory analysis.
    Comparison groups
    Fesomersen 40 mg v Placebo
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.612
    Method
    Logrank
    Parameter type
    Cause specific Hazard ratio
    Point estimate
    1.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.34
         upper limit
    6.08
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Fesomersen groups were compared to the placebo group using two-sided log-rank tests. Due to the exploratory nature of these analyses, no multiplicity adjustment was done. Cause-specific hazard ratio and corresponding 2-sided 95% confidence intervals, comparing the hazards for the event-of-interest in each of the Fesomersen groups with the placebo group were estimated based on three separate cause-specific Cox proportional hazards models as exploratory analysis.
    Comparison groups
    Fesomersen 80 mg v Placebo
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.757
    Method
    Logrank
    Parameter type
    Cause specific Hazard ratio
    Point estimate
    1.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.28
         upper limit
    5.66
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Fesomersen groups were compared to the placebo group using two-sided log-rank tests. Due to the exploratory nature of these analyses, no multiplicity adjustment was done. Cause-specific hazard ratio and corresponding 2-sided 95% confidence intervals, comparing the hazards for the event-of-interest in each of the Fesomersen groups with the placebo group were estimated based on three separate cause-specific Cox proportional hazards models as exploratory analysis.
    Comparison groups
    Fesomersen 120 mg v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.909
    Method
    Logrank
    Parameter type
    Cause specific Hazard ratio
    Point estimate
    0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.18
         upper limit
    4.52

    Secondary: Number of subjects with treatment-emergent adverse events (TEAEs) during the main treatment period and within the on-treatment time window and their severity

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    End point title
    Number of subjects with treatment-emergent adverse events (TEAEs) during the main treatment period and within the on-treatment time window and their severity
    End point description
    TEAEs were analyzed during the on-treatment time window within the main treatment period in the safety analysis set (SAF). Data observed from the randomization date until the end of the main treatment period. TEAEs were defined as events occurring after first study intervention administration and up to 20 weeks after last study intervention administration.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    Fesomersen 40 mg Fesomersen 80 mg Fesomersen 120 mg Placebo
    Number of subjects analysed
    77 [9]
    79 [10]
    76 [11]
    75 [12]
    Units: Subjects
        Any TEAE
    54
    56
    55
    55
        Maximum intensity for any TEAE: Mild
    28
    28
    22
    27
        Maximum intensity for any TEAE: Moderate
    17
    24
    28
    19
        Maximum intensity for any TEAE: Severe
    9
    4
    5
    9
    Notes
    [9] - SAF
    [10] - SAF
    [11] - SAF
    [12] - SAF
    No statistical analyses for this end point

    Secondary: Number of subjects with TEAEs during the main and extended treatment periods and within the on-treatment time window and their severity

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    End point title
    Number of subjects with TEAEs during the main and extended treatment periods and within the on-treatment time window and their severity
    End point description
    TEAEs were analyzed during during main and extended treatment periods in the safety analysis set (SAF). Data observed from the randomization date until the end of the extension treatment period. TEAEs were defined as events occurring after first study intervention administration and up to 20 weeks after last study intervention administration.
    End point type
    Secondary
    End point timeframe
    Up to 48 weeks
    End point values
    Fesomersen 40 mg Fesomersen 80 mg Fesomersen 120 mg Placebo
    Number of subjects analysed
    77 [13]
    79 [14]
    76 [15]
    75 [16]
    Units: Subjects
        Any TEAE
    61
    62
    58
    56
        Maximum intensity for any TEAE: Mild
    26
    25
    20
    26
        Maximum intensity for any TEAE: Moderate
    24
    31
    30
    18
        Maximum intensity for any TEAE: Severe
    11
    6
    8
    12
    Notes
    [13] - SAF
    [14] - SAF
    [15] - SAF
    [16] - SAF
    No statistical analyses for this end point

    Secondary: Number of subjects with TEAEs during the main and extended treatment periods and until 20 weeks after the last study intervention dose and their severity

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    End point title
    Number of subjects with TEAEs during the main and extended treatment periods and until 20 weeks after the last study intervention dose and their severity
    End point description
    TEAEs occurring from first study intervention intake until 20 weeks after last study intervention intake.
    End point type
    Secondary
    End point timeframe
    Up to 48 weeks
    End point values
    Fesomersen 40 mg Fesomersen 80 mg Fesomersen 120 mg Placebo
    Number of subjects analysed
    77 [17]
    79 [18]
    76 [19]
    75 [20]
    Units: Subjects
        Any TEAE
    64
    63
    62
    59
        Maximum intensity for any TEAE: Mild
    21
    21
    18
    21
        Maximum intensity for any TEAE: Moderate
    28
    33
    33
    22
        Maximum intensity for any TEAE: Severe
    15
    9
    11
    16
    Notes
    [17] - SAF
    [18] - SAF
    [19] - SAF
    [20] - SAF
    No statistical analyses for this end point

    Secondary: Trough concentrations (Ctrough) of three dose levels of fesomersen

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    End point title
    Trough concentrations (Ctrough) of three dose levels of fesomersen [21]
    End point description
    Trough (pre-dose) fesomersen-equivalent plasma concentrations (Ctrough) for 3 dose levels of fesomersen were summarized descriptively by dose level and visit: Visit 12, Visit 14, Visit 16, Visit 18 (main treatment period).
    End point type
    Secondary
    End point timeframe
    At visits V12 (Day 57), V14 (Day 85), V16 (Day 113), V18 (Day 141)
    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: Ctrough was not measured for the placebo group.
    End point values
    Fesomersen 40 mg Fesomersen 80 mg Fesomersen 120 mg
    Number of subjects analysed
    77 [22]
    79 [23]
    76 [24]
    Units: μg/mL
    geometric mean (geometric coefficient of variation)
        Visit 12 (n=62, 57, 55)
    0.000454 ± 118.753791
    0.000704 ± 80.938271
    0.001186 ± 76.691406
        Visit 14 (n=62, 60, 62)
    0.000490 ± 92.511801
    0.000792 ± 82.170296
    0.001246 ± 97.530820
        Visit 16 (n=58, 56, 60)
    0.000572 ± 85.974878
    0.000789 ± 68.188121
    0.001346 ± 81.805680
        Visit 18 (n=64, 53, 59)
    0.000521 ± 106.848825
    0.000828 ± 91.024162
    0.001424 ± 92.709743
    Notes
    [22] - PKS
    [23] - PKS
    [24] - PKS
    No statistical analyses for this end point

    Secondary: Maximum change in FXI (coagulation factor XI) antigen levels during the main treatment period

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    End point title
    Maximum change in FXI (coagulation factor XI) antigen levels during the main treatment period
    End point description
    The secondary endpoint of change in FXI antigen levels during the main treatment period was an optional secondary endpoint only as mentioned in the integrated clinical protocol amendment version 3.0 and was not analyzed in this study as the FXI activity assay is sufficient to describe the effect on FXI level in plasma.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    Fesomersen 40 mg Fesomersen 80 mg Fesomersen 120 mg Placebo
    Number of subjects analysed
    0 [25]
    0 [26]
    0 [27]
    0 [28]
    Units: U/mL
    arithmetic mean (standard deviation)
        Baseline
    ±
    ±
    ±
    ±
        Visit 5 (Day 1)
    ±
    ±
    ±
    ±
    Notes
    [25] - Not analyzed as the FXI activity assay is sufficient to describe the effect on FXI level in plasma.
    [26] - Not analyzed as the FXI activity assay is sufficient to describe the effect on FXI level in plasma.
    [27] - Not analyzed as the FXI activity assay is sufficient to describe the effect on FXI level in plasma.
    [28] - Not analyzed as the FXI activity assay is sufficient to describe the effect on FXI level in plasma.
    No statistical analyses for this end point

    Secondary: Maximum change in FXI activity levels during the main treatment period

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    End point title
    Maximum change in FXI activity levels during the main treatment period
    End point description
    The FXIa activity was measured by a fluorogenic activated FXIa activity (AXIA) assay. Absolute change from baseline at each visit until Visit 22 (Day 169) are reported.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    Fesomersen 40 mg Fesomersen 80 mg Fesomersen 120 mg Placebo
    Number of subjects analysed
    77 [29]
    79 [30]
    76 [31]
    75 [32]
    Units: U/mL
    arithmetic mean (standard deviation)
        Baseline
    0.00 ± 0.00
    0.00 ± 0.00
    0.00 ± 0.00
    0.00 ± 0.00
        Visit 5 (Day 1): Pre-dose
    0.06 ± 0.06
    0.05 ± 0.06
    0.05 ± 0.05
    0.04 ± 0.05
        Visit 5 (Day 1): 5 Hours
    0.09 ± 0.09
    0.11 ± 0.12
    0.13 ± 0.13
    0.10 ± 0.08
        Visit 6 (Day 2): 22 Hours
    0.13 ± 0.11
    0.12 ± 0.12
    0.15 ± 0.13
    0.14 ± 0.13
        Visit 7 (Day 8)
    0.21 ± 0.15
    0.32 ± 0.15
    0.43 ± 0.18
    0.08 ± 0.07
        Visit 8 (Day 15)
    0.34 ± 0.23
    0.48 ± 0.21
    0.61 ± 0.24
    0.12 ± 0.09
        Visit 9 (Day 22)
    0.37 ± 0.26
    0.50 ± 0.23
    0.63 ± 0.25
    0.11 ± 0.09
        Visit 10 (Day 29): Pre-dose
    0.34 ± 0.26
    0.44 ± 0.21
    0.60 ± 0.25
    0.09 ± 0.07
        Visit 10 (Day 29): 5 Hours
    0.32 ± 0.25
    0.43 ± 0.22
    0.58 ± 0.25
    0.12 ± 0.14
        Visit 11 (Day 43)
    0.47 ± 0.29
    0.59 ± 0.25
    0.76 ± 0.27
    0.09 ± 0.08
        Visit 12 (Day 57): Pre-dose
    0.42 ± 0.26
    0.55 ± 0.24
    0.69 ± 0.28
    0.11 ± 0.10
        Visit 13 (Day 71)
    0.52 ± 0.26
    0.66 ± 0.24
    0.76 ± 0.25
    0.15 ± 0.13
        Visit 14 (Day 85): Pre-dose
    0.46 ± 0.27
    0.59 ± 0.26
    0.72 ± 0.24
    0.14 ± 0.12
        Visit 16 (Day 113): Pre-dose
    0.46 ± 0.26
    0.57 ± 0.28
    0.75 ± 0.25
    0.16 ± 0.16
        Visit 18 (Day 141): Pre-dose
    0.47 ± 0.27
    0.56 ± 0.28
    0.72 ± 0.25
    0.12 ± 0.09
        Visit 19 (Day 148)
    0.52 ± 0.27
    0.63 ± 0.29
    0.76 ± 0.26
    0.15 ± 0.16
        Visit 20 (Day 155)
    0.52 ± 0.28
    0.65 ± 0.29
    0.77 ± 0.25
    0.15 ± 0.17
        Visit 21 (Day 162)
    0.50 ± 0.30
    0.64 ± 0.28
    0.75 ± 0.26
    0.16 ± 0.20
        Visit 22 (Day 169): Pre-dose
    0.46 ± 0.29
    0.59 ± 0.28
    0.73 ± 0.25
    0.17 ± 0.21
    Notes
    [29] - PDS
    [30] - PDS
    [31] - PDS
    [32] - PDS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first study intervention up to 64 Weeks.
    Adverse event reporting additional description
    Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study before the last contact, up to 64 Weeks.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Fesomersen 40 mg
    Reporting group description
    Subjects received subcutaneous treatment with 40 mg fesomersen.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received subcutaneous treatment with matching placebo to fesomersen.

    Reporting group title
    Fesomersen 120 mg
    Reporting group description
    Subjects received subcutaneous treatment with 120 mg fesomersen.

    Reporting group title
    Fesomersen 80 mg
    Reporting group description
    Subjects received subcutaneous treatment with 80 mg fesomersen.

    Serious adverse events
    Fesomersen 40 mg Placebo Fesomersen 120 mg Fesomersen 80 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 77 (24.68%)
    20 / 75 (26.67%)
    17 / 76 (22.37%)
    18 / 79 (22.78%)
         number of deaths (all causes)
    2
    7
    2
    1
         number of deaths resulting from adverse events
    1
    6
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial cancer
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic neoplasm
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superficial vein thrombosis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Renal transplant
         subjects affected / exposed
    3 / 77 (3.90%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    4 / 79 (5.06%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Swelling
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related thrombosis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella test positive
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transplant evaluation
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    0 / 77 (0.00%)
    3 / 75 (4.00%)
    2 / 76 (2.63%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shunt occlusion
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous graft thrombosis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula site complication
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous graft site haemorrhage
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shunt stenosis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular graft thrombosis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delayed graft function
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous graft site pseudoaneurysm
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post cardiac arrest syndrome
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spleen ischaemia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic ischaemia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 75 (2.67%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 75 (1.33%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular access site infection
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 77 (1.30%)
    2 / 75 (2.67%)
    4 / 76 (5.26%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 77 (2.60%)
    1 / 75 (1.33%)
    1 / 76 (1.32%)
    4 / 79 (5.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Fesomersen 40 mg Placebo Fesomersen 120 mg Fesomersen 80 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 77 (40.26%)
    21 / 75 (28.00%)
    30 / 76 (39.47%)
    27 / 79 (34.18%)
    Investigations
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    4 / 79 (5.06%)
         occurrences all number
    0
    0
    0
    4
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 77 (3.90%)
    7 / 75 (9.33%)
    6 / 76 (7.89%)
    5 / 79 (6.33%)
         occurrences all number
    5
    8
    8
    9
    Hypotension
         subjects affected / exposed
    6 / 77 (7.79%)
    1 / 75 (1.33%)
    8 / 76 (10.53%)
    4 / 79 (5.06%)
         occurrences all number
    27
    1
    12
    12
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 77 (5.19%)
    1 / 75 (1.33%)
    3 / 76 (3.95%)
    3 / 79 (3.80%)
         occurrences all number
    4
    1
    5
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 77 (5.19%)
    4 / 75 (5.33%)
    3 / 76 (3.95%)
    4 / 79 (5.06%)
         occurrences all number
    6
    5
    5
    9
    Thrombocytopenia
         subjects affected / exposed
    3 / 77 (3.90%)
    2 / 75 (2.67%)
    7 / 76 (9.21%)
    7 / 79 (8.86%)
         occurrences all number
    5
    4
    11
    13
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 77 (9.09%)
    4 / 75 (5.33%)
    2 / 76 (2.63%)
    3 / 79 (3.80%)
         occurrences all number
    8
    4
    3
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 77 (6.49%)
    2 / 75 (2.67%)
    3 / 76 (3.95%)
    2 / 79 (2.53%)
         occurrences all number
    9
    2
    3
    2
    Nausea
         subjects affected / exposed
    3 / 77 (3.90%)
    3 / 75 (4.00%)
    1 / 76 (1.32%)
    4 / 79 (5.06%)
         occurrences all number
    3
    3
    1
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 77 (2.60%)
    2 / 75 (2.67%)
    3 / 76 (3.95%)
    4 / 79 (5.06%)
         occurrences all number
    3
    3
    3
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 77 (5.19%)
    2 / 75 (2.67%)
    4 / 76 (5.26%)
    3 / 79 (3.80%)
         occurrences all number
    4
    5
    4
    3
    Muscle spasms
         subjects affected / exposed
    4 / 77 (5.19%)
    3 / 75 (4.00%)
    5 / 76 (6.58%)
    3 / 79 (3.80%)
         occurrences all number
    10
    13
    7
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2020
    This amendment was prepared to address the change in the new contraception guidance as requested by Health Authorities. Additionally, the number of procedures and visits was decreased to reduce the burden on the participants. This reduction does not impact the participants’ safety nor affect the benefit-risk assessment.
    07 Jul 2021
    The rationale of this amendment was to implement the possibility of local laboratory safety assessments in case centrally provided laboratory kits are not available due to COVID-19-related logistical reasons. Further it was to update the requirements for discontinuation of study intervention and the rules for prohibited medications intake. Minor corrections and clarifications were also added.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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