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    Clinical Trial Results:
    A Phase 2, Double-Blind, Placebo-Controlled, Randomized Study to Compare the Efficacy and Safety of Sotatercept (ACE-011) Versus Placebo When Added to Standard of Care for the Treatment of Pulmonary Arterial Hypertension (PAH)

    Summary
    EudraCT number
    		 2017-004738-27
    Trial protocol
    		 DE   BE   ES  
    Global end of trial date
    09 Mar 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    21 Jun 2023
    First version publication date
    22 Mar 2023
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    A011-09
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03496207
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Protocol: MK-7962-001
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.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 Mar 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Mar 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Study A011-09 is designed to assesses the efficacy and safety of sotatercept (ACE-011) relative to placebo in adults with pulmonary arterial hypertension (PAH). Eligible participants will receive study treatment for 24 weeks during the placebo-controlled treatment period, and then will be eligible to enroll into a 30-month extension period during which all participants will receive sotatercept. All treated patients will also undergo a follow-up period after last study drug treatment.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jun 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 26
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Israel: 8
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 27
    Worldwide total number of subjects
    106
    EEA total number of subjects
    33
    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)
    87
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study enrolled adults with pulmonary arterial hypertension (PAH). Other inclusion criteria applied.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo plus standard of care (SOC) by SC injection during the 24-week treatment period (Base Study; Cycles 1-8). Each cycle was 21 days. Dosing occurred once every 3 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Standard of Care (SOC)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection, Tablet, Inhalation solution
    Routes of administration
    Subcutaneous use, Oral use, Inhalation use, Intravenous use
    Dosage and administration details
    SOC therapy refers to approved PAH-specific medications and may consist of monotherapy or combination therapy with endothelin-receptor antagonists, phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin analogues or receptor agonists.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo once every 3 weeks

    Arm title
    		 Sotatercept 0.3 mg/kg
    Arm description
    		 Participants received sotatercept 0.3 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) and 30-month extension period (Cycles 9-51). Each cycle was 21 days. Dosing occurred once every 3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection, Tablet, Inhalation solution
    Routes of administration
    Subcutaneous use, Oral use, Inhalation use, Intravenous use
    Dosage and administration details
    SOC therapy refers to approved PAH-specific medications and may consist of monotherapy or combination therapy with endothelin-receptor antagonists, phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin analogues or receptor agonists.

    Investigational medicinal product name
    Sotatercept
    Investigational medicinal product code
    Other name
    ACE-011, MK-7962
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sotatercept 0.3 mg/kg once every three weeks

    Arm title
    		 Sotatercept 0.7 mg/kg
    Arm description
    		 Participants received sotatercept 0.7 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) and 30-month extension period (Cycles 9-51). Each cycle was 21 days. Dosing occurred once every 3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection, Tablet, Inhalation solution
    Routes of administration
    Subcutaneous use, Oral use, Inhalation use, Intravenous use
    Dosage and administration details
    SOC therapy refers to approved PAH-specific medications and may consist of monotherapy or combination therapy with endothelin-receptor antagonists, phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin analogues or receptor agonists.

    Investigational medicinal product name
    Sotatercept
    Investigational medicinal product code
    Other name
    ACE-011, MK-7962
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sotatercept 0.7 mg/kg once every three weeks

    Number of subjects in period 1
    		Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Started
    32
    32
    42
    Completed
    30
    31
    36
    Not completed
    2
    1
    6
         Adverse event, serious fatal
    -
    -
    1
         Consent withdrawn by subject
    1
    -
    1
         Adverse event, non-fatal
    1
    1
    4
    Period 2
    Period 2 title
    Extension Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Extension Period: Placebo→Sotatercept 0.3 mg/kg
    Arm description
    		 This treatment group represents participants from the Placebo arm who received placebo plus standard of care (SOC) by subcutaneous (SC) injection during the 24-week treatment period (Base Study; Cycles 1-8), then transitioned to the 30-month extension period (Cycles 9-51), during which they received sotatercept 0.3 mg/kg plus SOC by SC injection. Each cycle was 21 days. Dosing occurred once every 3 weeks.
    Arm type
    		 Placebo-crossed

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection, Tablet, Inhalation solution
    Routes of administration
    Subcutaneous use, Oral use, Inhalation use, Intravenous use
    Dosage and administration details
    SOC therapy refers to approved PAH-specific medications and may consist of monotherapy or combination therapy with endothelin-receptor antagonists, phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin analogues or receptor agonists.

    Investigational medicinal product name
    Sotatercept
    Investigational medicinal product code
    Other name
    ACE-011, MK-7962
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sotatercept 0.3 mg/kg once every three weeks

    Arm title
    		 Extension Period: Placebo→Sotatercept 0.7 mg/kg
    Arm description
    		 This treatment group represents participants from the Placebo arm who received placebo plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8), then transitioned to the 30-month extension period (Cycles 9-51), during which they received sotatercept 0.7 mg/kg plus SOC by SC injection. Each cycle was 21 days. Dosing occurred once every 3 weeks.
    Arm type
    		 Placebo-crossed

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection, Tablet, Inhalation solution
    Routes of administration
    Subcutaneous use, Oral use, Inhalation use, Intravenous use
    Dosage and administration details
    SOC therapy refers to approved PAH-specific medications and may consist of monotherapy or combination therapy with endothelin-receptor antagonists, phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin analogues or receptor agonists.

    Investigational medicinal product name
    Sotatercept
    Investigational medicinal product code
    Other name
    ACE-011, MK-7962
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sotatercept 0.7 mg/kg once every three weeks

    Arm title
    		 Extension Period: Sotatercept 0.3 mg/kg
    Arm description
    		 Participants received sotatercept 0.3 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) and 30-month extension period (Cycles 9-51). Each cycle was 21 days. Dosing occurred once every 3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection, Tablet, Inhalation solution
    Routes of administration
    Subcutaneous use, Oral use, Inhalation use, Intravenous use
    Dosage and administration details
    SOC therapy refers to approved PAH-specific medications and may consist of monotherapy or combination therapy with endothelin-receptor antagonists, phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin analogues or receptor agonists.

    Investigational medicinal product name
    Sotatercept
    Investigational medicinal product code
    Other name
    ACE-011, MK-7962
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sotatercept 0.3 mg/kg once every three weeks

    Arm title
    		 Extension Period: Sotatercept 0.7 mg/kg
    Arm description
    		 Participants received sotatercept 0.7 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) and 30-month extension period (Cycles 9-51). Each cycle was 21 days. Dosing occurred once every 3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection, Tablet, Inhalation solution
    Routes of administration
    Subcutaneous use, Oral use, Inhalation use, Intravenous use
    Dosage and administration details
    SOC therapy refers to approved PAH-specific medications and may consist of monotherapy or combination therapy with endothelin-receptor antagonists, phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin analogues or receptor agonists.

    Investigational medicinal product name
    Sotatercept
    Investigational medicinal product code
    Other name
    ACE-011, MK-7962
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sotatercept 0.7 mg/kg once every three weeks

    Number of subjects in period 2
    		Extension Period: Placebo→Sotatercept 0.3 mg/kg Extension Period: Placebo→Sotatercept 0.7 mg/kg Extension Period: Sotatercept 0.3 mg/kg Extension Period: Sotatercept 0.7 mg/kg
    Started
    15
    15
    31
    36
    Completed
    13
    15
    28
    31
    Not completed
    2
    0
    3
    5
         Adverse event, serious fatal
    1
    -
    1
    2
         Consent withdrawn by subject
    1
    -
    1
    1
         Adverse event, non-fatal
    -
    -
    1
    1
         Elevated hemoglobin levels
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo plus standard of care (SOC) by SC injection during the 24-week treatment period (Base Study; Cycles 1-8). Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Reporting group title
    Sotatercept 0.3 mg/kg
    Reporting group description
    		 Participants received sotatercept 0.3 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) and 30-month extension period (Cycles 9-51). Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Reporting group title
    Sotatercept 0.7 mg/kg
    Reporting group description
    		 Participants received sotatercept 0.7 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) and 30-month extension period (Cycles 9-51). Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Reporting group values
    		 Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg Total
    Number of subjects
    		 32 32 42 106
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 45.6 ( 13.38 ) 49.1 ( 14.34 ) 49.8 ( 15.05 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 26 29 37 92
        Male
    		 6 3 5 14
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 1
        Black or African American
    		 0 1 3 4
        White
    		 30 31 37 98
        More than one race
    		 1 0 1 2
        Unknown or Not Reported
    		 0 0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 10 9 13 32
        Not Hispanic or Latino
    		 21 19 28 68
        Unknown or Not Reported
    		 1 4 1 6

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo plus standard of care (SOC) by SC injection during the 24-week treatment period (Base Study; Cycles 1-8). Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Reporting group title
    Sotatercept 0.3 mg/kg
    Reporting group description
    		 Participants received sotatercept 0.3 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) and 30-month extension period (Cycles 9-51). Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Reporting group title
    Sotatercept 0.7 mg/kg
    Reporting group description
    		 Participants received sotatercept 0.7 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) and 30-month extension period (Cycles 9-51). Each cycle was 21 days. Dosing occurred once every 3 weeks.
    Reporting group title
    Extension Period: Placebo→Sotatercept 0.3 mg/kg
    Reporting group description
    		 This treatment group represents participants from the Placebo arm who received placebo plus standard of care (SOC) by subcutaneous (SC) injection during the 24-week treatment period (Base Study; Cycles 1-8), then transitioned to the 30-month extension period (Cycles 9-51), during which they received sotatercept 0.3 mg/kg plus SOC by SC injection. Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Reporting group title
    Extension Period: Placebo→Sotatercept 0.7 mg/kg
    Reporting group description
    		 This treatment group represents participants from the Placebo arm who received placebo plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8), then transitioned to the 30-month extension period (Cycles 9-51), during which they received sotatercept 0.7 mg/kg plus SOC by SC injection. Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Reporting group title
    Extension Period: Sotatercept 0.3 mg/kg
    Reporting group description
    		 Participants received sotatercept 0.3 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) and 30-month extension period (Cycles 9-51). Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Reporting group title
    Extension Period: Sotatercept 0.7 mg/kg
    Reporting group description
    		 Participants received sotatercept 0.7 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) and 30-month extension period (Cycles 9-51). Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Subject analysis set title
    Placebo-Crossed Treatment Group
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who received placebo plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) were re-randomized to receive either 0.3 mg/kg or 0.7 mg/kg of sotatercept plus SOC during 30-month extension period (Cycles 9-51). Per protocol, for Delayed-Start Analysis, the Placebo-Crossed Treatment Group included all participants who received 0.3 mg/kg plus SOC or 0.7 mg/kg of sotatercept plus SOC after a full course of placebo, regardless of their dose level. Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Subject analysis set title
    Continued Sotatercept Treatment Group
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who were randomized to receive either 0.3 mg/kg or 0.7 mg/kg of sotatercept plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) continued to receive sotatercept 0.3 mg/kg or 0.7 mg/kg plus SOC during the 30-month extension period (Cycles 9-51). Per protocol, for Delayed-Start Analysis, the Continued Sotatercept Treatment Group combined participants who received 0.3 mg/kg or 0.7 mg/kg of sotatercept plus SOC. Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Subject analysis set title
    Placebo-Crossed Treatment Group
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who received placebo plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) were re-randomized to receive either 0.3 mg/kg or 0.7 mg/kg of sotatercept plus SOC during 30-month extension period (Cycles 9-51). Per protocol, for Placebo-Crossed Analysis, the Placebo-Crossed Treatment Group included all participants who received 0.3 mg/kg plus SOC or 0.7 mg/kg of sotatercept plus SOC after a full course of placebo, regardless of their dose level. Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Subject analysis set title
    Placebo-Crossed treatment group
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who received placebo plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) were re-randomized to receive either 0.3 mg/kg or 0.7 mg/kg of sotatercept plus SOC during 30-month extension period (Cycles 9-51). Per protocol, for Delayed-Start Analysis, the Placebo-Crossed Treatment Group included all participants who received 0.3 mg/kg plus SOC or 0.7 mg/kg of sotatercept plus SOC after a full course of placebo, regardless of their dose level. Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Subject analysis set title
    Continued Sotatercept Treatment Group
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who were randomized to receive either 0.3 mg/kg or 0.7 mg/kg of sotatercept plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) continued to receive sotatercept 0.3 mg/kg or 0.7 mg/kg plus SOC during the 30-month extension period (Cycles 9-51). Per protocol, for Delayed-Start Analysis, the Continued Sotatercept Treatment Group combined participants who received 0.3 mg/kg or 0.7 mg/kg of sotatercept plus SOC. Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Subject analysis set title
    Placebo-Crossed Treatment Group
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who received placebo plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) were re-randomized to receive either 0.3 mg/kg or 0.7 mg/kg of sotatercept plus SOC during 30-month extension period (Cycles 9-51). Per protocol, for Placebo-Crossed Analysis, the Placebo-Crossed Treatment Group included all participants who received 0.3 mg/kg plus SOC or 0.7 mg/kg of sotatercept plus SOC after a full course of placebo, regardless of their dose level. Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Subject analysis set title
    Extension Period: Placebo→Sotatercept 0.3 mg/kg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    This treatment group represents participants from the Placebo arm who received placebo plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8), then transitioned to the 30-month extension period (Cycles 9-51), during which they received sotatercept 0.3 mg/kg plus SOC by SC injection. Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Subject analysis set title
    Extension Period: Placebo→Sotatercept 0.7 mg/kg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    This treatment group represents participants from the Placebo arm who received placebo plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8), then transitioned to the 30-month extension period (Cycles 9-51), during which they received sotatercept 0.7 mg/kg plus SOC by SC injection. Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Subject analysis set title
    Extension Period: Sotatercept 0.3 mg/kg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who received sotatercept 0.3 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) continued to receive sotatercept 0.3 mg/kg plus SOC during the 30-month extension period (Cycles 9-51). Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Subject analysis set title
    Extension Period: Sotatercept 0.7 mg/kg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who received sotatercept 0.7 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) continued to receive sotatercept 0.7 mg/kg plus SOC during the 30-month extension period (Cycles 9-51). Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Primary: Base Study: Change from Baseline in Pulmonary Vascular Resistance (PVR) at 24 Weeks

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    End point title
    		 Base Study: Change from Baseline in Pulmonary Vascular Resistance (PVR) at 24 Weeks
    End point description
    Each participant's PVR, at resting supine, was measured by right heart catheterization at baseline and at 24 weeks. The analysis population for this endpoint included all randomized participants administered their assigned treatment who received at least 6 of the same doses during Base Study, had baseline and post-Base Study PVR assessment and End of Treatment (EOT) assessment. Note: Data from participants whose dose was down-titrated were analyzed according to dose received at least 6 times rather than dose originally assigned. Per protocol, only participants who consistently received in 0.3 mg/kg or 0.7 mg/kg of sotatercept were planned to be analyzed.
    End point type
    Primary
    End point timeframe
    Baseline and 24 weeks
    End point values
    		 Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Number of subjects analysed
    30
    27
    30
    Units: dynes*sec/cm^5
    arithmetic mean (standard deviation)
        Change from Baseline in PVR at 24 Weeks
    -27.6 ( 251.08 )
    -168.4 ( 262.93 )
    -258.9 ( 169.42 )
        Baseline
    802.0 ( 331.05 )
    772.0 ( 285.62 )
    715.5 ( 267.11 )
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Analysis based on calculated LS means.
    Comparison groups
    Placebo v Sotatercept 0.7 mg/kg
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -269.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -365.81
         upper limit
    		 -173.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    48.48
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Analysis based on calculated LS means.
    Comparison groups
    Placebo v Sotatercept 0.3 mg/kg
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.003
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -151.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -249.59
         upper limit
    		 -52.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    49.53

    Primary: Extension Period: Change from Baseline in PVR (Delayed-Start Analysis)

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    End point title
    		 Extension Period: Change from Baseline in PVR (Delayed-Start Analysis)
    End point description
    Each participant's PVR, at resting supine, was measured by right heart catheterization at baseline and the timepoint at which the third right heart catheterization was performed, which occurred between Month 18 and Month 24. The analysis population for this endpoint included all randomized participants who received their assigned treatment, transitioned to the extension period, and had data for the respective timepoints.
    End point type
    Primary
    End point timeframe
    Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24
    End point values
    		 Placebo-Crossed Treatment Group Continued Sotatercept Treatment Group
    Number of subjects analysed
    30
    67
    Units: dynes*sec/cm^5
    arithmetic mean (standard deviation)
        Ext: Chg from BL in PVR (Delayed-Start Analysis)
    -246.9 ( 300.01 )
    -212.6 ( 254.24 )
        Baseline
    802.0 ( 331.05 )
    783.7 ( 371.59 )
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Analysis based on calculated LS means.
    Comparison groups
    Placebo-Crossed Treatment Group v Continued Sotatercept Treatment Group
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7851
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -13.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -113.85
         upper limit
    		 86.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    50.95

    Primary: Extension Period: Change from Baseline in PVR (Placebo-Crossed Analysis)

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    End point title
    		 Extension Period: Change from Baseline in PVR (Placebo-Crossed Analysis) [1]
    End point description
    Each participant's PVR, at resting supine, was measured by right heart catheterization at baseline and the timepoint at which the third right heart catheterization was performed, which occurred between Month 18 and Month 24. The analysis population for this endpoint included all randomized participants who received their assigned treatment, transitioned to the extension period, and had data for the respective timepoints.
    End point type
    Primary
    End point timeframe
    Baseline and the timepoint at which the third right heart catheterization was performed, which occurred between Month 18 and Month 24.
    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: There was no between-group statistical analysis calculated for this endpoint.
    End point values
    		 Placebo-Crossed Treatment Group
    Number of subjects analysed
    30
    Units: dynes*sec/cm^5
    arithmetic mean (standard deviation)
        Ext: Chg from BL in PVR (Placebo-Crossed Analysis)
    -246.9 ( 300.01 )
        Baseline
    802.0 ( 331.05 )
    No statistical analyses for this end point

    Primary: Extension Period: Number of Participants Who Discontinued Study Treatment Due to an AE

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    End point title
    		 Extension Period: Number of Participants Who Discontinued Study Treatment Due to an AE [2]
    End point description
    An AE is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The analysis population for this endpoint included all randomized participants who transitioned to the extension period and received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to 30 months
    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: There was no between-group statistical analysis calculated for this endpoint.
    End point values
    		 Extension Period: Placebo→Sotatercept 0.3 mg/kg Extension Period: Placebo→Sotatercept 0.7 mg/kg Extension Period: Sotatercept 0.3 mg/kg Extension Period: Sotatercept 0.7 mg/kg
    Number of subjects analysed
    15
    15
    31
    36
    Units: Participants
    1
    0
    1
    3
    No statistical analyses for this end point

    Primary: Extension Period: Number of Participants Who Experienced One or More Adverse Events (AEs)

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    End point title
    		 Extension Period: Number of Participants Who Experienced One or More Adverse Events (AEs) [3]
    End point description
    An AE is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The analysis population for this endpoint included all randomized participants who transitioned to the extension period and received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 32 months
    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: There was no between-group statistical analysis calculated for this endpoint.
    End point values
    		 Extension Period: Placebo→Sotatercept 0.3 mg/kg Extension Period: Placebo→Sotatercept 0.7 mg/kg Extension Period: Sotatercept 0.3 mg/kg Extension Period: Sotatercept 0.7 mg/kg
    Number of subjects analysed
    15
    15
    31
    36
    Units: Participants
    14
    15
    31
    36
    No statistical analyses for this end point

    Secondary: Base Study: Change from Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks

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    End point title
    		 Base Study: Change from Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks
    End point description
    6MWD is measured by an exercise test known as 6-Minute Walk Test (6MWT) that assesses aerobic capacity and endurance. It measures the distance covered over a time of 6 minutes and is used as an outcome measure by which to compare changes in performance capacity. Each participant’s 6MWD was measured at baseline and at 24 weeks. An increase in the distance walked during the 6MWT indicates improvement in basic mobility. The analysis population for this endpoint included all randomized participants administered their assigned treatment who received at least 6 of the same doses during Base Study, had baseline and post-Base Study PVR assessment and EOT assessment. Note: Data from participants whose dose was down-titrated were analyzed according to dose received at least 6 times rather than dose originally assigned. Per protocol, only participants who consistently received in 0.3 mg/kg or 0.7 mg/kg of sotatercept were planned to be analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and 24 weeks
    End point values
    		 Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Number of subjects analysed
    30
    27
    30
    Units: meters
        least squares mean (standard error)
    31.4 ( 9.69 )
    56.0 ( 10.07 )
    53.6 ( 9.84 )
    No statistical analyses for this end point

    Secondary: Base Study: Change from Baseline in Concentration of Amino-Terminal Brain Natriuretic Propeptide (NT-proBNP) at 24 Weeks

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    End point title
    		 Base Study: Change from Baseline in Concentration of Amino-Terminal Brain Natriuretic Propeptide (NT-proBNP) at 24 Weeks
    End point description
    Each participant's laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were measured at baseline and at 24 weeks. The analysis population for this endpoint included all randomized participants administered their assigned treatment who received ≥6 of the same doses during Base Study, had baseline and post-Base Study PVR assessment and EOT assessment, and had data for the outcome measure. Note: Data from participants whose dose was down-titrated were analyzed according to dose received ≥6 times rather than dose originally assigned. Per protocol, only participants who consistently received in 0.3 mg/kg or 0.7 mg/kg of sotatercept were planned to be analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and 24 Weeks
    End point values
    		 Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Number of subjects analysed
    29
    25
    28
    Units: pg/mL
        arithmetic mean (standard deviation)
    195.9 ( 726.46 )
    -718.2 ( 965.12 )
    -359.0 ( 757.58 )
    No statistical analyses for this end point

    Secondary: Base Study: Change from Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at 24 Weeks

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    End point title
    		 Base Study: Change from Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at 24 Weeks
    End point description
    Each participant's TAPSE, which is commonly used to evaluate tricuspid valve annulus movement as an indicator of right heart function, was measured by echocardiography at baseline and 24 weeks. The analysis population for this endpoint included all randomized participants administered their assigned treatment who received ≥6 of the same doses during Base Study, had baseline and post-Base Study PVR assessment and EOT assessment, and had data for the outcome measure. Note: Data from participants whose dose was down-titrated were analyzed according to dose received ≥6 times rather than dose originally assigned. Per protocol, only participants who consistently received in 0.3 mg/kg or 0.7 mg/kg of sotatercept were planned to be analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and 24 weeks
    End point values
    		 Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Number of subjects analysed
    28
    24
    28
    Units: cm
        arithmetic mean (standard deviation)
    0.0 ( 0.39 )
    0.1 ( 0.26 )
    -0.1 ( 0.34 )
    No statistical analyses for this end point

    Secondary: Base Study: Change from Baseline in 36-Item Short Form Health Survey (SF-36) Score

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    End point title
    		 Base Study: Change from Baseline in 36-Item Short Form Health Survey (SF-36) Score
    End point description
    The SF-36 questionnaire is a participant-reported survey evaluating 8 aspects of physical or mental health. The physical component scores range from 0-100; 100 represents the highest level of physical functioning. The mental component scores also range from 0-100; 100 represents the highest level of mental functioning. Each participant's SF-36 was recorded at baseline and on Day 1 of Cycle 9. Each cycle was 21 days. The analysis population for this endpoint included all randomized participants administered their assigned treatment who received ≥6 of the same doses during Base Study, had baseline and post-Base Study PVR assessment and EOT assessment, and had data for the outcome measure. Note: Data from participants whose dose was down-titrated were analyzed according to dose received ≥6 times rather than dose originally assigned. Per protocol, only participants who consistently received in 0.3 mg/kg or 0.7 mg/kg of sotatercept were planned to be analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
    End point values
    		 Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Number of subjects analysed
    30
    27
    29
    Units: Score on a scale
    least squares mean (standard error)
        Physical component
    3.5 ( 1.07 )
    4.5 ( 1.12 )
    3.1 ( 1.11 )
        Mental component
    3.2 ( 1.33 )
    3.6 ( 1.39 )
    0.0 ( 1.40 )
    No statistical analyses for this end point

    Secondary: Base Study: Change from Baseline in Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Score at Cycle 9

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    End point title
    		 Base Study: Change from Baseline in Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Score at Cycle 9
    End point description
    CAMPHOR is questionnaire with 65 items: 25 relate to symptoms, 25 to quality of life (QoL), 15 to activities. Symptom items are scored from 0-25; higher score indicates worse symptoms. QoL items are scored from 0-25; higher score indicates a worse QoL and greater functional limitation. Activity items are scored from 0-30; higher score indicates poorer functioning. Lowest combined score possible is 0. Highest combined score possible is 80. CAMPHOR scores were recorded at baseline and on Day 1 of Cycle 9. Analysis population: all randomized participants administered assigned treatment who received ≥6 of same doses during Base Study, had baseline and post-Base Study PVR assessment and EOT assessment, had data for outcome measure. Note: Data from participants whose dose was down-titrated were analyzed according to dose received ≥6 times rather than dose originally assigned. Per protocol, only participants who consistently received in 0.3 mg/kg or 0.7 mg/kg of sotatercept were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
    End point values
    		 Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Number of subjects analysed
    29
    23
    21
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -10.2 ( 12.91 )
    -6.9 ( 12.51 )
    -7.5 ( 7.96 )
    No statistical analyses for this end point

    Secondary: Base Study: Number of Participants Who Experienced Events Indicative of Clinical Worsening of Pulmonary Arterial Hypertension (PAH)

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    End point title
    		 Base Study: Number of Participants Who Experienced Events Indicative of Clinical Worsening of Pulmonary Arterial Hypertension (PAH)
    End point description
    Events that indicate clinical worsening of PAH include death, need for and/or worsening-related listing for lung and/or heart transplant, need to initiate an approved PAH SOC rescue therapy, PAH-specific hospitalization, or functional deterioration (worsened WHO Functional Class AND 15% decrease in 6MWD). The analysis population for this endpoint included all randomized participants who received their assigned treatment and had data for Base Study: Number of Participants Who Experienced Events Indicative of Clinical Worsening of PAH.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Number of subjects analysed
    32
    32
    42
    Units: Participants
    2
    0
    1
    No statistical analyses for this end point

    Secondary: Base Study: Number of Participants Who Experienced One or More AEs

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    End point title
    		 Base Study: Number of Participants Who Experienced One or More AEs
    End point description
    An AE is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Number of subjects analysed
    32
    32
    42
    Units: Participants
    29
    29
    35
    No statistical analyses for this end point

    Secondary: Base Study: Number of Participants Who Experienced an Improvement from Baseline in World Health Organization (WHO) Functional Class at 24 Weeks

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    End point title
    		 Base Study: Number of Participants Who Experienced an Improvement from Baseline in World Health Organization (WHO) Functional Class at 24 Weeks
    End point description
    The WHO Functional Class describes the severity of a person's pulmonary hypertension symptoms. There are four different classes: I is the mildest and IV the most severe form of pulmonary hypertension. The analysis population for this endpoint included all randomized participants who received their assigned treatment and at least 6 of the same doses during Base Study, had baseline and post-Base Study PVR assessment and EOT assessment, and had data for Base Study: Number of Participants Who Experienced an Improvement from Baseline in WHO Functional Class at 24 Weeks. Note: Data from participants whose dose was down-titrated were analyzed according to dose received at least 6 times rather than dose to which originally assigned.
    End point type
    Secondary
    End point timeframe
    Baseline and 24 Weeks
    End point values
    		 Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Number of subjects analysed
    30
    27
    30
    Units: Participants
    4
    8
    6
    No statistical analyses for this end point

    Secondary: Base Study: Number of Participants Who Discontinued Study Treatment Due to an AE

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    End point title
    		 Base Study: Number of Participants Who Discontinued Study Treatment Due to an AE
    End point description
    An AE is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Number of subjects analysed
    32
    32
    42
    Units: Participants
    1
    1
    5
    No statistical analyses for this end point

    Secondary: Base Study: Change from Baseline in Body Mass Index (BMI) at Cycle 9

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    End point title
    		 Base Study: Change from Baseline in Body Mass Index (BMI) at Cycle 9
    End point description
    Each participant's BMI was measured at baseline and at 24 weeks. The analysis population for this endpoint included all randomized participants who received their assigned treatment and had data for Base Study: Change from Baseline in BMI at Cycle 9.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
    End point values
    		 Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Number of subjects analysed
    30
    31
    36
    Units: kg/m^2
        arithmetic mean (standard deviation)
    -0.2 ( 1.25 )
    0.6 ( 0.89 )
    0.2 ( 1.07 )
    No statistical analyses for this end point

    Secondary: Base Study: Change from Baseline in Systolic and Diastolic Blood Pressure at Cycle 9

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    End point title
    		 Base Study: Change from Baseline in Systolic and Diastolic Blood Pressure at Cycle 9
    End point description
    Each participant's systolic and diastolic blood pressure was taken at baseline and on Day 1 of Cycle 9. Each cycle was 21 days. The analysis population for this endpoint included all randomized participants who received their assigned treatment and had data for Base Study: Change from Baseline in Systolic and Diastolic Blood Pressure at Cycle 9.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
    End point values
    		 Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Number of subjects analysed
    30
    31
    36
    Units: mmHg
    arithmetic mean (standard deviation)
        Systolic blood pressure
    -0.8 ( 10.06 )
    3.4 ( 11.75 )
    2.6 ( 12.28 )
        Diastolic blood pressure
    2.3 ( 8.06 )
    4.1 ( 8.64 )
    1.7 ( 8.69 )
    No statistical analyses for this end point

    Secondary: Base Study: Change from Baseline in Respiratory Rate at Cycle 9

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    End point title
    		 Base Study: Change from Baseline in Respiratory Rate at Cycle 9
    End point description
    Each participant's respiratory rate (number of breaths per minute) was measured at baseline and on Day 1 of Cycle 9. Each cycle was 21 days. The analysis population for this endpoint included all randomized participants who received their assigned treatment and had data for Base Study: Change from Baseline in Respiratory Rate at Cycle 9.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
    End point values
    		 Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Number of subjects analysed
    29
    31
    36
    Units: breaths/min
        arithmetic mean (standard deviation)
    -0.3 ( 2.10 )
    -1.3 ( 3.72 )
    -0.3 ( 3.05 )
    No statistical analyses for this end point

    Secondary: Extension Period: Change from Baseline in 6MWD (Delayed-Start Analysis)

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    End point title
    		 Extension Period: Change from Baseline in 6MWD (Delayed-Start Analysis)
    End point description
    6MWD is measured by an exercise test known as 6MWT that assesses aerobic capacity and endurance. It measures the distance covered over a time of 6 minutes and is used as an outcome measure by which to compare changes in performance capacity. Each participant’s 6MWD was measured at baseline and the timepoint at which the third RCH was performed. This occurred between Month 18 and Month 24, at which time each participant's 6MWD was also measured. An increase in the distance walked during the 6MWT indicates improvement in basic mobility. The analysis population for this endpoint included all randomized participants who received their assigned treatment, transitioned to the extension period, and had data for Extension Period: Change from Baseline in 6MWD (Delayed-Start Analysis).
    End point type
    Secondary
    End point timeframe
    Baseline and the timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24
    End point values
    		 Placebo-Crossed Treatment Group Continued Sotatercept Treatment Group
    Number of subjects analysed
    30
    67
    Units: meters
        least squares mean (standard error)
    60.1 ( 14.35 )
    55.7 ( 9.47 )
    No statistical analyses for this end point

    Secondary: Base Study: Change from Baseline in QTcF Interval at Cycle 9

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    End point title
    		 Base Study: Change from Baseline in QTcF Interval at Cycle 9
    End point description
    Each participant's QTcF Interval was measured at baseline and on Day 1 of Cycle 9. The analysis population for this endpoint included all randomized participants who received their assigned treatment and had data for Base Study: Change from Baseline in QTcF Interval at Cycle 9.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
    End point values
    		 Placebo Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Number of subjects analysed
    30
    31
    35
    Units: milliseconds
        arithmetic mean (standard deviation)
    0.7 ( 31.10 )
    -7.4 ( 20.57 )
    -9.1 ( 31.55 )
    No statistical analyses for this end point

    Secondary: Base Study: Maximum Plasma Concentration (Cmax) of Sotatercept

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    End point title
    		 Base Study: Maximum Plasma Concentration (Cmax) of Sotatercept [4]
    End point description
    Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Based on population pharmacokinetic (PopPK) modeling of previous sotatercept studies, Cmax occurs at Day 8 of Cycle 1 after a sotatercept dose is given. The sotatercept concentration at Day 8 of Cycle 1 (each cycle was 21 days) is presented here as Cmax. The analysis population for this endpoint included all randomized participants who received at least 1 dose of sotatercept and had sufficient pharmacokinetic samples collected and assayed for PK analysis.
    End point type
    Secondary
    End point timeframe
    Day 8 of Cycle 1 (Each cycle was 21 days.)
    Notes
    [4] - 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: The Placebo arm was not included in the PK analysis.
    End point values
    		 Sotatercept 0.3 mg/kg Sotatercept 0.7 mg/kg
    Number of subjects analysed
    32
    42
    Units: ng/mL
        arithmetic mean (standard deviation)
    1910.3 ( 715.86 )
    4598.5 ( 1622.59 )
    No statistical analyses for this end point

    Secondary: Extension Period: Change from Baseline in 6MWD (Placebo-Crossed Analysis)

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    End point title
    		 Extension Period: Change from Baseline in 6MWD (Placebo-Crossed Analysis)
    End point description
    6MWD is measured by an exercise test known as 6MWT that assesses aerobic capacity and endurance. It measures the distance covered over a time of 6 minutes and is used as an outcome measure by which to compare changes in performance capacity. Each participant’s 6MWD was measured at baseline and the timepoint at which the third right heart catheterization was performed. This occurred between Month 18 and Month 24, at which time each participant's 6MWD was also measured. An increase in the distance walked during the 6MWT indicates improvement in basic mobility. The analysis population for this endpoint included all randomized participants who received their assigned treatment, transitioned to the extension period, and had data for Extension Period: Change from Baseline in 6MWD (Placebo-Crossed Analysis).
    End point type
    Secondary
    End point timeframe
    Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24
    End point values
    		 Placebo-Crossed Treatment Group
    Number of subjects analysed
    30
    Units: meters
        arithmetic mean (standard error)
    60.5 ( 13.21 )
    No statistical analyses for this end point

    Secondary: Extension Period: Number of Participants Who Experienced an Improvement from Baseline in WHO Functional Class (Delayed-Start Analysis)

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    End point title
    		 Extension Period: Number of Participants Who Experienced an Improvement from Baseline in WHO Functional Class (Delayed-Start Analysis)
    End point description
    The WHO Functional Class describes the severity of a person's pulmonary hypertension symptoms. There are four different classes: I is the mildest and IV the most severe form of pulmonary hypertension. Each participant’s WHO Functional Class was assessed at baseline and the timepoint at which the third right heart catheterization was performed. This occurred between Month 18 and Month 24, at which time each participant's WHO Functional Class was also assessed. The analysis population for this endpoint included all randomized participants who received their assigned treatment, transitioned to the extension period, and had data for Extension Period: Number of Participants Who Experienced an Improvement from Baseline in WHO Functional Class (Delayed-Start Analysis).
    End point type
    Secondary
    End point timeframe
    Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24
    End point values
    		 Placebo-Crossed treatment group Continued Sotatercept Treatment Group
    Number of subjects analysed
    29
    66
    Units: Participants
    16
    27
    No statistical analyses for this end point

    Secondary: Extension Period: Change from Baseline in WHO Functional Class (Placebo-Crossed Analysis)

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    End point title
    		 Extension Period: Change from Baseline in WHO Functional Class (Placebo-Crossed Analysis)
    End point description
    The WHO Functional Class describes the severity of a person's pulmonary hypertension symptoms. There are four different classes: I is the mildest and IV the most severe form of pulmonary hypertension. Each participant’s WHO Functional Class was assessed at baseline and the timepoint at which the third right heart catheterization was performed. This occurred between Month 18 and Month 24, at which time each participant's WHO Functional Class was also assessed. The analysis population for this endpoint included all randomized participants who received their assigned treatment, transitioned to the extension period, and had data for Extension Period: Change from Baseline in WHO Functional Class (Placebo-Crossed Analysis).
    End point type
    Secondary
    End point timeframe
    Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24
    End point values
    		 Placebo-Crossed Treatment Group
    Number of subjects analysed
    28
    Units: WHO functional class
        arithmetic mean (standard deviation)
    -0.6 ( 0.74 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment period: Up to 24 weeks; Extension period: Up to approximately 32 months.
    Adverse event reporting additional description
    The safety analysis population included all participants who received at least 1 dose of study treatment. The analysis population for Deaths (all causes) included all randomized participants.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Base Study: Placebo
    Reporting group description
    		 Participants received placebo plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8). Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Reporting group title
    Base Study: Sotatercept 0.3 mg/kg
    Reporting group description
    		 Participants received sotatercept 0.3 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8). Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Reporting group title
    Base Study: Sotatercept 0.7 mg/kg
    Reporting group description
    		 Participants received sotatercept 0.7 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8). Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Reporting group title
    Extension Period: Placebo→Sotatercept 0.3 mg/kg
    Reporting group description
    		 This treatment group represents participants from the Placebo arm who received placebo plus standard of care (SOC) by subcutaneous (SC) injection during the 24-week treatment period (Base Study; Cycles 1-8), then transitioned to the 30-month extension period (Cycles 9-51), during which they received sotatercept 0.3 mg/kg plus SOC by SC injection. Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Reporting group title
    Extension Period: Placebo→Sotatercept 0.7 mg/kg
    Reporting group description
    		 This treatment group represents participants from the Placebo arm who received placebo plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8), then transitioned to the 30-month extension period (Cycles 9-51), during which they received sotatercept 0.7 mg/kg plus SOC by SC injection. Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Reporting group title
    Extension Period: Sotatercept 0.3 mg/kg
    Reporting group description
    		 Participants who received sotatercept 0.3 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) continued to receive sotatercept 0.3 mg/kg plus SOC during the 30-month extension period (Cycles 9-51). Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Reporting group title
    Extension Period: Sotatercept 0.7 mg/kg
    Reporting group description
    		 Participants who received sotatercept 0.7 mg/kg plus SOC by SC injection during the 24-week treatment period (Base Study; Cycles 1-8) continued to receive sotatercept 0.7 mg/kg plus SOC during the 30-month extension period (Cycles 9-51). Each cycle was 21 days. Dosing occurred once every 3 weeks.

    Serious adverse events
    		 Base Study: Placebo Base Study: Sotatercept 0.3 mg/kg Base Study: Sotatercept 0.7 mg/kg Extension Period: Placebo→Sotatercept 0.3 mg/kg Extension Period: Placebo→Sotatercept 0.7 mg/kg Extension Period: Sotatercept 0.3 mg/kg Extension Period: Sotatercept 0.7 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 32 (9.38%)
    2 / 32 (6.25%)
    10 / 42 (23.81%)
    6 / 15 (40.00%)
    4 / 15 (26.67%)
    10 / 31 (32.26%)
    12 / 36 (33.33%)
         number of deaths (all causes)
    0
    0
    1
    1
    0
    1
    2
         number of deaths resulting from adverse events
    0
    0
    0
    1
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon neoplasm
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vessel puncture site haematoma
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Red blood cell count increased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia paroxysmal
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Chorioretinopathy
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Systemic lupus erythematosus
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Brain abscess
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Bronchitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion site infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic embolus
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Base Study: Placebo Base Study: Sotatercept 0.3 mg/kg Base Study: Sotatercept 0.7 mg/kg Extension Period: Placebo→Sotatercept 0.3 mg/kg Extension Period: Placebo→Sotatercept 0.7 mg/kg Extension Period: Sotatercept 0.3 mg/kg Extension Period: Sotatercept 0.7 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 32 (78.13%)
    29 / 32 (90.63%)
    33 / 42 (78.57%)
    14 / 15 (93.33%)
    15 / 15 (100.00%)
    30 / 31 (96.77%)
    36 / 36 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    4 / 31 (12.90%)
    3 / 36 (8.33%)
         occurrences all number
    0
    1
    0
    0
    2
    4
    3
    Haematoma
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    0
    1
    2
    0
    1
    Flushing
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    1 / 31 (3.23%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    1
    0
    2
    1
    4
    Deep vein thrombosis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hypotension
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    2 / 42 (4.76%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    2 / 31 (6.45%)
    1 / 36 (2.78%)
         occurrences all number
    2
    2
    2
    0
    12
    2
    2
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    2
    1
    1
    0
    2
    Asthenia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    3 / 15 (20.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    1
    4
    1
    0
    2
    Catheter site haemorrhage
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Chest discomfort
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    0
    Application site pain
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    2
    1
    0
    1
    0
    1
    0
    Cyst
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Discomfort
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Face oedema
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    1
    Fatigue
         subjects affected / exposed
    6 / 32 (18.75%)
    2 / 32 (6.25%)
    4 / 42 (9.52%)
    6 / 15 (40.00%)
    4 / 15 (26.67%)
    6 / 31 (19.35%)
    5 / 36 (13.89%)
         occurrences all number
    6
    2
    4
    7
    5
    9
    6
    Localised oedema
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Infusion site pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Injection site erythema
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    1
    Injection site pain
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    4 / 42 (9.52%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    4
    0
    0
    1
    2
    Injection site pruritus
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    0
    Feeling abnormal
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 42 (2.38%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    5 / 31 (16.13%)
    3 / 36 (8.33%)
         occurrences all number
    0
    1
    1
    2
    0
    5
    3
    Vessel puncture site haematoma
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    3 / 15 (20.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    5
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    2 / 31 (6.45%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    1
    2
    1
    4
    2
    Oedema peripheral
         subjects affected / exposed
    5 / 32 (15.63%)
    3 / 32 (9.38%)
    5 / 42 (11.90%)
    4 / 15 (26.67%)
    6 / 15 (40.00%)
    11 / 31 (35.48%)
    7 / 36 (19.44%)
         occurrences all number
    5
    3
    6
    4
    6
    12
    8
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Breast hyperplasia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Breast swelling
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Heavy menstrual bleeding
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    1
    Vaginal ulceration
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Vulvovaginal dryness
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    2 / 31 (6.45%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    2
    0
    1
    5
    1
    Nasal congestion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    3 / 15 (20.00%)
    1 / 15 (6.67%)
    1 / 31 (3.23%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    1
    3
    1
    1
    2
    Cough
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    3 / 15 (20.00%)
    4 / 31 (12.90%)
    1 / 36 (2.78%)
         occurrences all number
    2
    2
    0
    4
    4
    4
    1
    Dyspnoea
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    3 / 15 (20.00%)
    3 / 15 (20.00%)
    5 / 31 (16.13%)
    3 / 36 (8.33%)
         occurrences all number
    3
    2
    0
    4
    6
    8
    3
    Dyspnoea exertional
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 32 (12.50%)
    5 / 42 (11.90%)
    3 / 15 (20.00%)
    4 / 15 (26.67%)
    7 / 31 (22.58%)
    4 / 36 (11.11%)
         occurrences all number
    1
    5
    6
    7
    5
    10
    5
    Nasal dryness
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Nasal turbinate hypertrophy
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    3 / 15 (20.00%)
    2 / 31 (6.45%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    0
    4
    4
    2
    1
    Productive cough
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    1
    Pulmonary hypertension
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    1 / 36 (2.78%)
         occurrences all number
    2
    0
    0
    1
    0
    1
    1
    Pulmonary mass
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    2
    Respiratory failure
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Rhinitis allergic
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    2
    Rhinorrhoea
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    1
    Wheezing
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    1
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    1 / 42 (2.38%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
    2 / 31 (6.45%)
    1 / 36 (2.78%)
         occurrences all number
    2
    2
    1
    3
    3
    2
    1
    Depression
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    5 / 31 (16.13%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    2
    0
    5
    1
    Insomnia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    3
    Procedural anxiety
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Device leakage
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Device dislocation
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Investigations
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    2 / 42 (4.76%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    2
    0
    0
    2
    3
    Haematocrit increased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Blood sodium decreased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Blood pressure increased
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Blood chloride increased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Intraocular pressure increased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Reticulocyte count increased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 31 (3.23%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    1
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    2
    Haemoglobin increased
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    7 / 42 (16.67%)
    1 / 15 (6.67%)
    5 / 15 (33.33%)
    0 / 31 (0.00%)
    5 / 36 (13.89%)
         occurrences all number
    0
    1
    7
    1
    7
    0
    5
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    0
    Contusion
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 31 (3.23%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    1
    Epicondylitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Fall
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    5 / 31 (16.13%)
    0 / 36 (0.00%)
         occurrences all number
    1
    1
    0
    0
    2
    5
    0
    Head injury
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    1
    Limb injury
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Tendon rupture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Tooth fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Toxicity to various agents
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Post-traumatic neck syndrome
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Road traffic accident
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Vaccination complication
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    2 / 31 (6.45%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    0
    4
    4
    2
    5
    Procedural pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Bradycardia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    Low cardiac output syndrome
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Palpitations
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 32 (3.13%)
    1 / 42 (2.38%)
    2 / 15 (13.33%)
    3 / 15 (20.00%)
    2 / 31 (6.45%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    1
    2
    4
    4
    1
    Pericardial effusion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    1
    Right ventricular failure
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    0
    Cardiac failure
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    Tachycardia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 31 (3.23%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    1
    Tachycardia paroxysmal
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Lethargy
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    1
    0
    Facial paralysis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    6 / 32 (18.75%)
    8 / 32 (25.00%)
    6 / 42 (14.29%)
    4 / 15 (26.67%)
    7 / 15 (46.67%)
    9 / 31 (29.03%)
    6 / 36 (16.67%)
         occurrences all number
    10
    16
    8
    21
    13
    16
    10
    Hypoaesthesia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Intention tremor
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    3 / 32 (9.38%)
    5 / 32 (15.63%)
    4 / 42 (9.52%)
    4 / 15 (26.67%)
    2 / 15 (13.33%)
    4 / 31 (12.90%)
    5 / 36 (13.89%)
         occurrences all number
    4
    5
    5
    5
    2
    6
    6
    Sciatica
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    Presyncope
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    1 / 31 (3.23%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    0
    6
    1
    1
    Paraesthesia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 42 (2.38%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    4 / 36 (11.11%)
         occurrences all number
    0
    2
    1
    1
    0
    1
    5
    Migraine
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    1
    2
    0
    0
    Syncope
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    3
    1
    0
    1
    0
    0
    2
    Tremor
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Tension headache
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    2 / 42 (4.76%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    8 / 31 (25.81%)
    1 / 36 (2.78%)
         occurrences all number
    3
    2
    2
    0
    2
    13
    2
    Blood loss anaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    4 / 15 (26.67%)
    1 / 31 (3.23%)
    3 / 36 (8.33%)
         occurrences all number
    2
    1
    0
    0
    5
    1
    3
    Polycythaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
    0 / 31 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    1
    0
    2
    2
    0
    3
    Leukopenia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    5
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Leukocytosis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    2
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    5 / 42 (11.90%)
    3 / 15 (20.00%)
    1 / 15 (6.67%)
    3 / 31 (9.68%)
    3 / 36 (8.33%)
         occurrences all number
    0
    3
    8
    3
    2
    3
    8
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Vertigo
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 32 (6.25%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    3 / 31 (9.68%)
    0 / 36 (0.00%)
         occurrences all number
    1
    2
    0
    1
    0
    3
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    2
    Cataract
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    5
    Dacryostenosis acquired
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Deposit eye
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Glaucoma
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Keratitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Periorbital oedema
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Defaecation urgency
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    3 / 31 (9.68%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    4
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    1
    0
    2
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    3 / 31 (9.68%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    1
    Crohn's disease
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    0
    Dental plaque
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    5 / 32 (15.63%)
    7 / 32 (21.88%)
    6 / 42 (14.29%)
    3 / 15 (20.00%)
    5 / 15 (33.33%)
    9 / 31 (29.03%)
    5 / 36 (13.89%)
         occurrences all number
    6
    8
    6
    3
    7
    14
    5
    Dry mouth
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    2 / 42 (4.76%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    2
    1
    0
    1
    1
    Dyspepsia
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
    0 / 31 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    0
    0
    4
    2
    0
    2
    Gastritis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 31 (3.23%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    0
    1
    3
    1
    Nausea
         subjects affected / exposed
    5 / 32 (15.63%)
    3 / 32 (9.38%)
    5 / 42 (11.90%)
    3 / 15 (20.00%)
    4 / 15 (26.67%)
    9 / 31 (29.03%)
    5 / 36 (13.89%)
         occurrences all number
    9
    4
    5
    3
    9
    11
    7
    Gingival bleeding
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    0
    Haematochezia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Large intestine polyp
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    1 / 31 (3.23%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    2
    1
    1
    2
    Peptic ulcer
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Proctalgia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    5
    0
    Vomiting
         subjects affected / exposed
    4 / 32 (12.50%)
    3 / 32 (9.38%)
    3 / 42 (7.14%)
    1 / 15 (6.67%)
    3 / 15 (20.00%)
    6 / 31 (19.35%)
    4 / 36 (11.11%)
         occurrences all number
    10
    3
    3
    3
    4
    9
    5
    Hepatobiliary disorders
    Gallbladder polyp
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    1
    Ecchymosis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    Dermal cyst
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Acne
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Telangiectasia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    4 / 15 (26.67%)
    5 / 15 (33.33%)
    5 / 31 (16.13%)
    7 / 36 (19.44%)
         occurrences all number
    0
    0
    0
    5
    6
    5
    8
    Skin lesion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    1
    Rosacea
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    0
    Rash
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    1
    0
    0
    5
    0
    2
    Pruritus
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    1 / 36 (2.78%)
         occurrences all number
    2
    2
    0
    1
    0
    1
    1
    Hidradenitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Erythema
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    2
    0
    0
    2
    0
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    3 / 31 (9.68%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    1
    Microalbuminuria
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    0
    Haematuria
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    2
    Calculus urinary
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 32 (15.63%)
    2 / 32 (6.25%)
    1 / 42 (2.38%)
    2 / 15 (13.33%)
    5 / 15 (33.33%)
    8 / 31 (25.81%)
    5 / 36 (13.89%)
         occurrences all number
    5
    2
    1
    2
    9
    12
    5
    Back pain
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 32 (9.38%)
    1 / 42 (2.38%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
    7 / 31 (22.58%)
    2 / 36 (5.56%)
         occurrences all number
    2
    3
    1
    1
    3
    10
    3
    Bursitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Exostosis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    0
    Fracture pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    Joint swelling
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    Muscle spasms
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    4 / 42 (9.52%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
    4 / 31 (12.90%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    4
    1
    2
    4
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 32 (6.25%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    1 / 36 (2.78%)
         occurrences all number
    1
    2
    0
    0
    0
    2
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    1
    Pain in jaw
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    2
    0
    Pain in extremity
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 32 (9.38%)
    5 / 42 (11.90%)
    2 / 15 (13.33%)
    3 / 15 (20.00%)
    8 / 31 (25.81%)
    3 / 36 (8.33%)
         occurrences all number
    2
    4
    6
    6
    3
    11
    4
    Neck pain
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 32 (6.25%)
    3 / 42 (7.14%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
    4 / 31 (12.90%)
    4 / 36 (11.11%)
         occurrences all number
    1
    2
    3
    1
    2
    4
    4
    Tendonitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    2 / 31 (6.45%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
    3 / 31 (9.68%)
    3 / 36 (8.33%)
         occurrences all number
    0
    1
    0
    1
    2
    3
    4
    Conjunctivitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    1
    Cystitis
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    3 / 31 (9.68%)
    5 / 36 (13.89%)
         occurrences all number
    0
    0
    0
    2
    1
    3
    6
    Ear infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    3
    Fungal pharyngitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    4 / 42 (9.52%)
    2 / 15 (13.33%)
    2 / 15 (13.33%)
    5 / 31 (16.13%)
    2 / 36 (5.56%)
         occurrences all number
    2
    3
    4
    2
    2
    5
    2
    Gingivitis
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Onychomycosis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Hordeolum
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    5 / 36 (13.89%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    5
    Labyrinthitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 32 (3.13%)
    4 / 42 (9.52%)
    5 / 15 (33.33%)
    6 / 15 (40.00%)
    10 / 31 (32.26%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    4
    9
    7
    14
    1
    Herpes zoster
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    0
    Oral herpes
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    1
    Otitis externa
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    0
    Tooth infection
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    3
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    4
    1
    2
    0
    Sinusitis
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    3 / 15 (20.00%)
    2 / 31 (6.45%)
    3 / 36 (8.33%)
         occurrences all number
    0
    2
    0
    2
    5
    3
    4
    Tinea pedis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Tonsillitis bacterial
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    3 / 15 (20.00%)
    2 / 15 (13.33%)
    2 / 31 (6.45%)
    1 / 36 (2.78%)
         occurrences all number
    3
    0
    1
    4
    2
    3
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 32 (9.38%)
    4 / 32 (12.50%)
    2 / 42 (4.76%)
    3 / 15 (20.00%)
    1 / 15 (6.67%)
    6 / 31 (19.35%)
    6 / 36 (16.67%)
         occurrences all number
    4
    5
    2
    3
    1
    9
    8
    Urinary tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 32 (9.38%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    5 / 31 (16.13%)
    5 / 36 (13.89%)
         occurrences all number
    0
    3
    0
    2
    1
    7
    5
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 31 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 31 (3.23%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    4
    Gout
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 42 (0.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    1
    2
    0
    6
    1
    2
    0
    Folate deficiency
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    Fluid retention
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    2 / 31 (6.45%)
    1 / 36 (2.78%)
         occurrences all number
    3
    0
    0
    1
    1
    3
    1
    Dyslipidaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    0 / 31 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    1
    Decreased appetite
         subjects affected / exposed
    3 / 32 (9.38%)
    2 / 32 (6.25%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    3
    2
    1
    0
    2
    4
    0
    Iron deficiency
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    3 / 15 (20.00%)
    2 / 15 (13.33%)
    3 / 31 (9.68%)
    6 / 36 (16.67%)
         occurrences all number
    1
    0
    1
    6
    2
    3
    8
    Hypomagnesaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 42 (2.38%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    3
    0
    Hypervolaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    1 / 31 (3.23%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 31 (6.45%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    Hypokalaemia
         subjects affected / exposed
    4 / 32 (12.50%)
    3 / 32 (9.38%)
    5 / 42 (11.90%)
    3 / 15 (20.00%)
    0 / 15 (0.00%)
    4 / 31 (12.90%)
    1 / 36 (2.78%)
         occurrences all number
    4
    3
    5
    5
    0
    8
    1
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    0 / 42 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 31 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Feb 2018
    Amendment 01A: Revisions to the following sections: Synopsis, Overall Design, Study Design, Schedule of Events, Objectives and Endpoints, Pharmacodynamics, Exclusion Criteria, Six-Minute-Walk Distance, Clinical Worsening.
    05 May 2018
    Amendment 02A: Revisions to the following sections: Schedule of Events, Inclusion Criteria, Treatment Administration and Schedule, Interim Analysis, Appendix 7: Genetics.
    27 Dec 2018
    Amendment 05A: Revisions to the following items or sections: Table 1, Schedule of Events, Study Design, Figure 1, Study Rationale, Overall Design, Dose Modification, Randomization and Blinding, Efficacy Assessments, Populations for Analyses, Sample Size Determination, Inclusion Criteria, Exclusions Criteria, Standard of Care Therapy, Interim Analysis, Benefit/Risk Assessment, Screen Failures, Discontinuation of Study Treatment, Adverse Events, Safety Assessments, Electrocardiograms, Clinical Safety Laboratory Assessments, Appendix 6: Contraceptive Guidance and Collection of Pregnancy Information, Appendix 8: National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
    11 Mar 2020
    Amendment 06A: Extended treatment by adding additional cycles 35 to 51 (a 1-year extension), additional evaluations and safety monitoring, dose modification adjustments; also updated the blinding process.
    21 Aug 2020
    Amendment 07A: Revisions to the following sections: Synopsis, Overall Design, Schedule of Events, Dose Modification, Pulmonary Vascular Resistance by Right Heart Catheterization, and Statistical Analysis.

    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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