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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Compare the Efficacy and Safety of Sotatercept Versus Placebo When Added to Background Pulmonary Arterial Hypertension (PAH) Therapy for the Treatment of PAH

    Summary
    EudraCT number
    		 2020-004142-11
    Trial protocol
    		 DE   SE   FR   BE   NL   AT   PL   CZ   IT  
    Global end of trial date
    06 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Nov 2023
    First version publication date
    26 Nov 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    7962-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04576988
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck: MK-7962-003
    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
    06 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Aug 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objectives of this study are to evaluate the efficacy and safety of sotatercept (MK-7962) treatment (plus background pulmonary arterial hypertension (PAH) therapy) versus placebo (plus background PAH therapy) at 24 weeks in adults with PAH. The primary hypothesis of the study is that the participants receiving sotatercept will have improved 6-minute walk distance (6MWD) at 24 weeks compared to participants receiving placebo.
    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
    		 Background pulmonary arterial hypertension (PAH) therapy refers to combination therapy consisting of drugs from two or more of the following drug classes: an endothelin-receptor antagonist (ERA), a phosphodiesterase 5(PDE5) inhibitor, a soluble guanylate cyclase stimulator, and/or a prostacyclin analogue or receptor agonist.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jan 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Brazil: 26
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Czechia: 5
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Germany: 71
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    Serbia: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 88
    Worldwide total number of subjects
    323
    EEA total number of subjects
    161
    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)
    269
    From 65 to 84 years
    54
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Of the 324 randomized participants, 1 participant was randomized in error and did not receive study treatment and no data was collected. Hence, the results are presented on 323 participants.

    Pre-assignment
    Screening details
    		 Per protocol, not all participants from the double-blind placebo controlled (DBPC) period entered the long-term double blind (LTDB) period due to clinical worsening or consent withdrawal after DBPC period.

    Period 1
    Period 1 title
    Double Blind Placebo Controlled (DBPC)
    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
    		 Sotatercept plus background PAH therapy
    Arm description
    		 Participants received a starting dose of sotatercept 0.3 mg/kg titrated up to 0.7mg/kg by subcutaneous (SC) injection every 21 days plus background PAH therapy during the double-blind placebo controlled (DBPC) period for up to approximately 24 weeks. After 24 weeks, participants received sotatercept dose titrated up to 0.7mg/kg SC injection every 21 days plus background PAH therapy during the long-term double blind (LTDB) period for up to approximately 72 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Background PAH Therapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Inhalation solution, Powder for injection
    Routes of administration
    Subcutaneous use, Oral use, Inhalation use, Intravenous use
    Dosage and administration details
    Background PAH therapy refers to combination therapy consisting of drugs from two or more of the following drug classes: an endothelin-receptor antagonist (ERA), a phosphodiesterase 5(PDE5) inhibitor, a soluble guanylate cyclase stimulator, and/or a prostacyclin analogue or receptor agonist.

    Investigational medicinal product name
    Sotatercept
    Investigational medicinal product code
    Other name
    MK-7962 ACE-011
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sotatercept at a starting dose of 0.3 mg/kg with a target dose of 0.7 mg/kg administered subcutaneously (SC) every 21 days plus background PAH therapy.

    Arm title
    		 Placebo plus background PAH therapy
    Arm description
    		 Participants received dose matched placebo by SC injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks and the LTDB period for up to approximately 72 weeks.
    Arm type
    		 Placebo

    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 administered subcutaneously (SC) every 21 days plus background PAH therapy.

    Investigational medicinal product name
    Background PAH Therapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Inhalation solution, Powder for injection
    Routes of administration
    Subcutaneous use, Oral use, Inhalation use, Intravenous use
    Dosage and administration details
    Background PAH therapy refers to combination therapy consisting of drugs from two or more of the following drug classes: an endothelin-receptor antagonist (ERA), a phosphodiesterase 5(PDE5) inhibitor, a soluble guanylate cyclase stimulator, and/or a prostacyclin analogue or receptor agonist.

    Number of subjects in period 1
    		Sotatercept plus background PAH therapy Placebo plus background PAH therapy
    Started
    163
    160
    Treated
    163
    160
    Completed
    159
    148
    Not completed
    4
    12
         Adverse event, serious fatal
    -
    5
         Consent withdrawn by subject
    2
    3
         Adverse event, non-fatal
    1
    1
         Clinical worsening event
    -
    2
         Protocol deviation
    1
    1
    Period 2
    Period 2 title
    Long Term Double Blind (LTDB)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sotatercept plus background PAH therapy
    Arm description
    		 Participants received a starting dose of sotatercept 0.3 mg/kg titrated up to 0.7mg/kg by subcutaneous (SC) injection every 21 days plus background PAH therapy during the double-blind placebo controlled (DBPC) period for up to approximately 24 weeks. After 24 weeks, participants received sotatercept dose titrated up to 0.7mg/kg SC injection every 21 days plus background PAH therapy during the long-term double blind (LTDB) period for up to approximately 72 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Background PAH Therapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Inhalation solution, Powder for injection
    Routes of administration
    Oral use, Inhalation use, Subcutaneous use, Intravenous use
    Dosage and administration details
    Background PAH therapy refers to combination therapy consisting of drugs from two or more of the following drug classes: an endothelin-receptor antagonist (ERA), a phosphodiesterase 5(PDE5) inhibitor, a soluble guanylate cyclase stimulator, and/or a prostacyclin analogue or receptor agonist.

    Investigational medicinal product name
    Sotatercept
    Investigational medicinal product code
    Other name
    MK-7962 ACE-011
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sotatercept at a starting dose of 0.3 mg/kg with a target dose of 0.7 mg/kg administered subcutaneously (SC) every 21 days plus background PAH therapy.

    Arm title
    		 Placebo plus background PAH therapy
    Arm description
    		 Participants received dose matched placebo by SC injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks and the LTDB period for up to approximately 72 weeks.
    Arm type
    		 Placebo

    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 administered subcutaneously (SC) every 21 days plus background PAH therapy.

    Investigational medicinal product name
    Background PAH Therapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Inhalation solution, Powder for injection
    Routes of administration
    Oral use, Inhalation use, Subcutaneous use, Intravenous use
    Dosage and administration details
    Background PAH therapy refers to combination therapy consisting of drugs from two or more of the following drug classes: an endothelin-receptor antagonist (ERA), a phosphodiesterase 5(PDE5) inhibitor, a soluble guanylate cyclase stimulator, and/or a prostacyclin analogue or receptor agonist.

    Number of subjects in period 2 [1]
    		Sotatercept plus background PAH therapy Placebo plus background PAH therapy
    Started
    159
    142
    Treated
    158
    142
    Completed
    155
    136
    Not completed
    4
    6
         Adverse event, serious fatal
    2
    1
         Consent withdrawn by subject
    -
    3
         Adverse event, non-fatal
    2
    -
         Sponsor decision
    -
    1
         Protocol deviation
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all participants entered LTDB period.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Sotatercept plus background PAH therapy
    Reporting group description
    		 Participants received a starting dose of sotatercept 0.3 mg/kg titrated up to 0.7mg/kg by subcutaneous (SC) injection every 21 days plus background PAH therapy during the double-blind placebo controlled (DBPC) period for up to approximately 24 weeks. After 24 weeks, participants received sotatercept dose titrated up to 0.7mg/kg SC injection every 21 days plus background PAH therapy during the long-term double blind (LTDB) period for up to approximately 72 weeks.

    Reporting group title
    Placebo plus background PAH therapy
    Reporting group description
    		 Participants received dose matched placebo by SC injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks and the LTDB period for up to approximately 72 weeks.

    Reporting group values
    		 Sotatercept plus background PAH therapy Placebo plus background PAH therapy Total
    Number of subjects
    		 163 160 323
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 47.6 ± 14.09 48.3 ± 15.50 -
    Sex: Female, Male
    Units: Participants
        Female
    		 129 127 256
        Male
    		 34 33 67
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 1 6 7
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 2 5 7
        White
    		 147 141 288
        More than one race
    		 7 4 11
        Unknown or Not Reported
    		 6 2 8
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 27 31 58
        Not Hispanic or Latino
    		 132 124 256
        Unknown or Not Reported
    		 4 5 9
    World Health Organization (WHO) functional class (FC) II or III at baseline
    WHO FC was used to rate how ill a pulmonary arterial hypertension (PAH) participant was. Class II: Participants with PAH resulting in a slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class III: Participants with PAH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope
    Units: Subjects
        Class II
    		 79 78 157
        Class III
    		 84 82 166
    Background PAH Therapy at Baseline
    Background PAH therapy refers to approved PAH-specific medications and may consist of monotherapy or combination therapy (double or triple therapy) with endothelin-receptor antagonist (ERA), a phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin analogues or receptor agonists.
    Units: Subjects
        Monotherapy
    		 9 4 13
        Double therapy
    		 56 56 112
        Triple therapy
    		 98 100 198
    6-Minute Walk Distance (6MWD) at baseline
    The 6MWD is the distance walked in 6 minutes as a measure of functional capacity.
    Units: meters
        arithmetic mean (standard deviation)
    		 397.6 ± 84.28 404.7 ± 80.59 -
    Subject analysis sets

    Subject analysis set title
    Sotatercept plus background PAH therapy (DBPC period)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a starting dose of sotatercept 0.3 mg/kg titrated up to 0.7mg/kg by subcutaneous (SC) injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks.

    Subject analysis set title
    Placebo plus background PAH therapy (DBPC period)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received dose matched placebo by SC injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks.

    Subject analysis set title
    Sotatercept plus background PAH therapy (DBPC period)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a starting dose of sotatercept 0.3 mg/kg titrated up to 0.7mg/kg by subcutaneous (SC) injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks.

    Subject analysis set title
    Placebo plus background PAH therapy (DBPC period)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received dose matched placebo SC injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks.

    Subject analysis set title
    Placebo plus background PAH therapy (DPBC period)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received dose matched placebo SC injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks.

    Subject analysis set title
    Placebo plus background PAH therapy (DBPC period)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received dose matched placebo SC injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks.

    Subject analysis sets values
    		 Sotatercept plus background PAH therapy (DBPC period) Placebo plus background PAH therapy (DBPC period) Sotatercept plus background PAH therapy (DBPC period) Placebo plus background PAH therapy (DBPC period) Placebo plus background PAH therapy (DPBC period) Placebo plus background PAH therapy (DBPC period)
    Number of subjects
    163
    160
    162
    159
    160
    160
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    34.4 ±
    1.0 ±
    38.9 ±
    10.1 ±
    58.6 ±
    0.01 ±
    Sex: Female, Male
    Units: Participants
        Female
        Male
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Native Hawaiian or Other Pacific Islander
        Black or African American
        White
        More than one race
        Unknown or Not Reported
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    World Health Organization (WHO) functional class (FC) II or III at baseline
    WHO FC was used to rate how ill a pulmonary arterial hypertension (PAH) participant was. Class II: Participants with PAH resulting in a slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class III: Participants with PAH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope
    Units: Subjects
        Class II
        Class III
    Background PAH Therapy at Baseline
    Background PAH therapy refers to approved PAH-specific medications and may consist of monotherapy or combination therapy (double or triple therapy) with endothelin-receptor antagonist (ERA), a phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin analogues or receptor agonists.
    Units: Subjects
        Monotherapy
        Double therapy
        Triple therapy
    6-Minute Walk Distance (6MWD) at baseline
    The 6MWD is the distance walked in 6 minutes as a measure of functional capacity.
    Units: meters
        arithmetic mean (standard deviation)
    34.4 ±
    1.0 ±
    38.9 ±
    10.1 ±
    58.6 ±
    0.01 ±

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Sotatercept plus background PAH therapy
    Reporting group description
    		 Participants received a starting dose of sotatercept 0.3 mg/kg titrated up to 0.7mg/kg by subcutaneous (SC) injection every 21 days plus background PAH therapy during the double-blind placebo controlled (DBPC) period for up to approximately 24 weeks. After 24 weeks, participants received sotatercept dose titrated up to 0.7mg/kg SC injection every 21 days plus background PAH therapy during the long-term double blind (LTDB) period for up to approximately 72 weeks.

    Reporting group title
    Placebo plus background PAH therapy
    Reporting group description
    		 Participants received dose matched placebo by SC injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks and the LTDB period for up to approximately 72 weeks.
    Reporting group title
    Sotatercept plus background PAH therapy
    Reporting group description
    		 Participants received a starting dose of sotatercept 0.3 mg/kg titrated up to 0.7mg/kg by subcutaneous (SC) injection every 21 days plus background PAH therapy during the double-blind placebo controlled (DBPC) period for up to approximately 24 weeks. After 24 weeks, participants received sotatercept dose titrated up to 0.7mg/kg SC injection every 21 days plus background PAH therapy during the long-term double blind (LTDB) period for up to approximately 72 weeks.

    Reporting group title
    Placebo plus background PAH therapy
    Reporting group description
    		 Participants received dose matched placebo by SC injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks and the LTDB period for up to approximately 72 weeks.

    Subject analysis set title
    Sotatercept plus background PAH therapy (DBPC period)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a starting dose of sotatercept 0.3 mg/kg titrated up to 0.7mg/kg by subcutaneous (SC) injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks.

    Subject analysis set title
    Placebo plus background PAH therapy (DBPC period)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received dose matched placebo by SC injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks.

    Subject analysis set title
    Sotatercept plus background PAH therapy (DBPC period)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a starting dose of sotatercept 0.3 mg/kg titrated up to 0.7mg/kg by subcutaneous (SC) injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks.

    Subject analysis set title
    Placebo plus background PAH therapy (DBPC period)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received dose matched placebo SC injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks.

    Subject analysis set title
    Placebo plus background PAH therapy (DPBC period)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received dose matched placebo SC injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks.

    Subject analysis set title
    Placebo plus background PAH therapy (DBPC period)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received dose matched placebo SC injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks.

    Primary: Number of Participants Who Experienced an Adverse Event (AE)

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    End point title
    		 Number of Participants Who Experienced an Adverse Event (AE) [1]
    End point description
    An AE was any untoward medical occurrence in a study participant administered a study drug, which did not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it was considered related to the study drug. Per protocol, the number of participants who reported an AE were reported for DBPC period. The analysis population included all randomized participants who received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 24 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical analysis planned for this endpoint.
    End point values
    		 Sotatercept plus background PAH therapy (DBPC period) Placebo plus background PAH therapy (DBPC period)
    Number of subjects analysed
    163
    160
    Units: Participants
    138
    140
    No statistical analyses for this end point

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

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    End point title
    		 Number of Participants Who Discontinued Study Treatment Due to an AE [2]
    End point description
    An AE was any untoward medical occurrence in a study participant administered a study drug, which did not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it was considered related to the study drug. Per protocol, the number of participants who discontinued study treatment due to an AE were reported for DBPC period. The analysis population included all randomized participants who received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 24 weeks
    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 statistical analysis planned for this endpoint.
    End point values
    		 Sotatercept plus background PAH therapy (DBPC period) Placebo plus background PAH therapy (DBPC period)
    Number of subjects analysed
    163
    160
    Units: Participants
    3
    10
    No statistical analyses for this end point

    Primary: Change From Baseline in 6-Minute Walk Distance (6MWD) at Week 24

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    End point title
    		 Change From Baseline in 6-Minute Walk Distance (6MWD) at Week 24
    End point description
    The 6MWD was the distance walked in 6 minutes as a measure of functional capacity. This was assessed using the 6-minute walk test (6MWT). Per protocol, change from baseline in 6MWD at Week 24 was reported for DBPC period. The analysis population included all randomized participants who received at least one dose of study treatment and had a baseline value of 6MWD.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Sotatercept plus background PAH therapy (DBPC period) Placebo plus background PAH therapy (DBPC period)
    Number of subjects analysed
    163
    160
    Units: meters
        median (full range (min-max))
    34.4 (32.5 to 35.5)
    1.0 (-1.0 to 5.0)
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Sotatercept plus background PAH therapy (DBPC period) v Placebo plus background PAH therapy (DBPC period)
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 < 0.001 [4]
    Method
    		 Aligned Rank Stratified Wilcoxon (ARSW)
    Parameter type
    		 Treatment difference
    Point estimate
    40.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 27.53
         upper limit
    		 54.14
    Notes
    [3] - Hodges-Lehmann location-shift estimate of the overall treatment difference with 95% confidence interval (CI) was reported.
    [4] - A 2-sided p-value was calculated using ARSW test with WHO FC II/III and background PAH therapy as strata.

    Secondary: Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 24

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    End point title
    		 Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 24
    End point description
    PVR is a hemodynamic variable of pulmonary circulation and was measured by right heart catheterization (RHC). Per protocol, the change from baseline in PVR at Week 24 was reported for DBPC period. The analysis population included all randomized participants who received at least one dose of study treatment and who had a baseline measurement for the PVR.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Sotatercept plus background PAH therapy (DBPC period) Placebo plus background PAH therapy (DBPC period)
    Number of subjects analysed
    163
    160
    Units: dynes*sec/cm^5
        median (full range (min-max))
    -165.1 (-184.0 to -152.0)
    32.8 (24.0 to 40.0)
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Sotatercept plus background PAH therapy (DBPC period) v Placebo plus background PAH therapy (DBPC period)
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 < 0.001 [6]
    Method
    		 ARSW test
    Parameter type
    		 Treatment difference
    Point estimate
    -234.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -288.37
         upper limit
    		 -180.75
    Notes
    [5] - Hodges-Lehmann location-shift estimate of the overall treatment difference with 95% CI was reported.
    [6] - A 2-sided p-value was calculated using ARSW test with WHO FC II/III and background PAH therapy as strata.

    Secondary: Change From Baseline in the Percentage of Participants Achieving Multicomponent Improvement at Week 24

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    End point title
    		 Change From Baseline in the Percentage of Participants Achieving Multicomponent Improvement at Week 24
    End point description
    Multicomponent Improvement was defined as consisting of all of the following: (a) Improvement in 6MWD (increase ≥30 meters) (b) Improvement in N-terminal pro b-type natriuretic peptide (NT-proBNP; decrease in NT-proBNP ≥30%) or maintenance/achievement of NT-proBNP level <300 ng/L (c) Improvement in World Health Organization (WHO) Functional Class (FC) or maintenance of WHO FC II. Per protocol, change from baseline in the percentage of participants achieving multicomponent improvement at Week 24 was reported for DBPC period. The analysis population included All randomized participants who received at least one dose of study treatment and who had a baseline measurement for the multicomponent improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Sotatercept plus background PAH therapy (DBPC period) Placebo plus background PAH therapy (DBPC period)
    Number of subjects analysed
    162
    159
    Units: Percent change
        number (not applicable)
    38.9
    10.1
    Statistical analysis title
    		 Probability of multicomponent improvement
    Comparison groups
    Sotatercept plus background PAH therapy (DBPC period) v Placebo plus background PAH therapy (DBPC period)
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [7] - A 2-sided p-value was calculated using Cochran-Mantel-Haenszel (CMH) method with WHO FC II/III and background PAH therapy as strata.

    Secondary: Change From Baseline in the Percentage of Participants Who Improve in WHO FC at Week 24

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    End point title
    		 Change From Baseline in the Percentage of Participants Who Improve in WHO FC at Week 24
    End point description
    The severity of participant's pulmonary arterial hypertension (PAH) symptoms will be graded using the WHO FC system. WHO functional classification for PAH ranges from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). Participants who improve in WHO FC were classified into "Improved", "No change" and "Worsened". Improvement = reduction in FC, worsened = increase in FC and no change = no change in FC. Per protocol, change from baseline in the percentage of participants who improve in WHO FC at Week 24 were reported for DBPC period. The analysis population included all randomized participants who received at least one dose of study treatment and who had a baseline measurement for the WHO FC.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Sotatercept plus background PAH therapy (DBPC period) Placebo plus background PAH therapy (DBPC period)
    Number of subjects analysed
    163
    159
    Units: Percent change
        number (not applicable)
    29.4
    13.8
    Statistical analysis title
    		 Probability of who improve in WHO FC
    Comparison groups
    Sotatercept plus background PAH therapy (DBPC period) v Placebo plus background PAH therapy (DBPC period)
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [8] - A 2-sided p-value was calculated using CMH method with WHO FC II/III and background PAH therapy as strata.

    Secondary: Change From Baseline in NT-proBNP Levels at Week 24

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    End point title
    		 Change From Baseline in NT-proBNP Levels at Week 24
    End point description
    NT-proBNP is a circulating biomarker that reflects myocardial stretch. Per protocol, the change from baseline in NT-proBNP level at Week 24 was reported for DBPC period. The analysis population included all randomized participants who received at least one dose of study treatment and who had a baseline measurement for the NT-proBNP levels.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Sotatercept plus background PAH therapy (DBPC period) Placebo plus background PAH therapy (DPBC period)
    Number of subjects analysed
    163
    160
    Units: pg/mL
        median (full range (min-max))
    -230.3 (-236.0 to -223.0)
    58.6 (44.0 to 73.0)
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Sotatercept plus background PAH therapy (DBPC period) v Placebo plus background PAH therapy (DPBC period)
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    P-value
    		 < 0.001 [10]
    Method
    		 ARSW test
    Parameter type
    		 Treatment difference
    Point estimate
    -441.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -573.54
         upper limit
    		 -309.61
    Notes
    [9] - Hodges-Lehmann location-shift estimate of the overall treatment difference with 95% CI was reported.
    [10] - A 2-sided p-value was calculated using ARSW test with WHO FC II/III and background PAH therapy as strata.

    Secondary: Time to Death or the First Occurrence of Clinical Worsening Event

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    End point title
    		 Time to Death or the First Occurrence of Clinical Worsening Event
    End point description
    Clinical Worsening events are defined as any of the following: worsening-related listing for lung and/or heart transplant; need to initiate rescue therapy with an approved background PAH therapy or the need to increase the dose of infusion prostacyclin by 10% or more; need for atrial septostomy; hospitalization for worsening of PAH (≥ 24 hours); or deterioration of PAH defined by both of the following events occurring at any time: worsened WHO FC and decrease in 6MWD by ≥15% confirmed by 2 tests at least 4 hours apart, but no more than 1 week. Per protocol, time to death or the first occurrence of clinical worsening event was reported. The analysis population included all randomized participants who received at least one dose of study treatment and who died or experienced a first clinical worsening event.
    End point type
    Secondary
    End point timeframe
    Up to approximately 18 months
    End point values
    		 Sotatercept plus background PAH therapy Placebo plus background PAH therapy
    Number of subjects analysed
    163
    160
    Units: Weeks
        median (standard deviation)
    9999 ± 9999
    9999 ± 9999
    Statistical analysis title
    		 Hazard Ratio
    Comparison groups
    Sotatercept plus background PAH therapy v Placebo plus background PAH therapy
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.163
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.076
         upper limit
    		 0.347
    Notes
    [11] - A 2-sided p-value was calculated using Log rank test with WHO FC II/III and background PAH therapy as strata.

    Secondary: Change From Baseline in Percentage of Participants Who Maintain or Achieve a Low Risk Score Using the Simplified French Risk Score Calculator at Week 24

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    End point title
    		 Change From Baseline in Percentage of Participants Who Maintain or Achieve a Low Risk Score Using the Simplified French Risk Score Calculator at Week 24
    End point description
    The simplified French risk scoring system was based on the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension (PH). In this study, the noninvasive parameters were used to determine the score. 'Low risk' was defined as attaining or maintaining all 3 low-risk criteria: WHO FC I or II, 6MWD > 440 m, and NT-proBNP <300 ng/L. Per protocol, change from baseline in percentage of participants who maintained or achieved a low risk score using the simplified French risk score calculator at Week 24 was reported for DBPC period. The analysis population included all randomized participants who received at least one dose of study treatment and who had a baseline measurement for the low risk score.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Sotatercept plus background PAH therapy (DBPC period) Placebo plus background PAH therapy (DBPC period)
    Number of subjects analysed
    162
    159
    Units: Percent Change
        number (not applicable)
    39.5
    18.2
    Statistical analysis title
    		 Probability
    Comparison groups
    Sotatercept plus background PAH therapy (DBPC period) v Placebo plus background PAH therapy (DBPC period)
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Change From Baseline in the Physical Impacts Domain Score of Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT®) at Week 24

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    End point title
    		 Change From Baseline in the Physical Impacts Domain Score of Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT®) at Week 24
    End point description
    The PAH SYMPACT is a 23-item questionnaire to measure pulmonary arterial hypertension (PAH)-related symptoms and impact of PAH on daily life. The physical impact domain consists of walking slowly on flat surface, walking quickly on flat surface, walking uphill, carrying things, doing light indoor household chores, washing, or dressing oneself, and needing help from others. Participants were asked to recall and report on each item experienced in past 7 days. Each item score ranges from 0 (not difficult at all) to 4 (extremely difficult). Domain score was calculated by summing individual responses for each item and dividing by number of impact items (range: 0=no physical impact to 4=severe physical impact). Higher score indicated more severe physical impact. Change from baseline in physical impacts domain score at Week 24 was reported for DBPC period. Analysis population included all randomized participants who received at least 1 dose of study treatment and had baseline domain score.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Sotatercept plus background PAH therapy (DBPC period) Placebo plus background PAH therapy (DBPC period)
    Number of subjects analysed
    163
    160
    Units: Score on a scale
        median (full range (min-max))
    -0.13 (-0.15 to 0.00)
    0.01 (0.00 to 0.14)
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Sotatercept plus background PAH therapy (DBPC period) v Placebo plus background PAH therapy (DBPC period)
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.01 [12]
    Method
    		 ARSW test
    Parameter type
    		 Treatment difference
    Point estimate
    -0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 -0.04
    Notes
    [12] - A 2-sided p-value was calculated using ARSW test with WHO FC II/III and background PAH therapy as strata.

    Secondary: Change From Baseline in the Cardiopulmonary Symptoms Domain Score of PAH-SYMPACT® at Week 24

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    End point title
    		 Change From Baseline in the Cardiopulmonary Symptoms Domain Score of PAH-SYMPACT® at Week 24
    End point description
    The PAH SYMPACT is a 23-item questionnaire to measure PAH-related symptoms and impact of PAH on daily life. The cardiopulmonary symptoms consist of shortness of breath, fatigue, lack of energy, swelling in the ankles or legs, swelling in the stomach area, and cough. Participants were asked to recall and report on each item experienced in past 7 days. Each item score ranges from 0 (no symptom at all) to 4 (very severe symptoms). Mean individual symptom item score was determined for each of the 6 items and a domain score was calculated by summing the mean individual symptom item scores and dividing by the number of items (range: 0=no cardiopulmonary symptoms to 4=severe cardiopulmonary symptoms). Higher score indicated more severe symptoms experienced. Change from baseline in the cardiopulmonary domain score at Week 24 was reported for DBPC period. Analysis population included all randomized participants who received at least 1 dose of study treatment and had a baseline domain score.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Sotatercept plus background PAH therapy (DBPC period) Placebo plus background PAH therapy (DBPC period)
    Number of subjects analysed
    163
    160
    Units: Score on a scale
        median (full range (min-max))
    -0.12 (-0.14 to -0.06)
    -0.01 (-0.03 to 0.02)
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Sotatercept plus background PAH therapy (DBPC period) v Placebo plus background PAH therapy (DBPC period)
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.028 [13]
    Method
    		 ARSW test
    Parameter type
    		 Treatment difference
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.256
         upper limit
    		 -0.014
    Notes
    [13] - A 2-sided p-value was calculated using ARSW test with WHO FC II/III and background PAH therapy as strata.

    Secondary: Change From Baseline in the Cognitive/Emotional Impacts Domain Score of PAH-SYMPACT® at Week 24

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    End point title
    		 Change From Baseline in the Cognitive/Emotional Impacts Domain Score of PAH-SYMPACT® at Week 24
    End point description
    The PAH SYMPACT is a 23-item questionnaire to measure PAH-related symptoms and impact of PAH on daily life. The Cognitive/Emotional Impact domain consists of thinking clearly, feeling sad, feeling worried, and feeling frustrated. Participants were asked to recall and report on each item experienced in past 7 days. Score for each item ranges from 0 (not difficult at all) to 4 (extremely difficult). A domain score was calculated by summing the individual responses for each item and dividing by the number of impact items (range: 0=no cognitive/emotional impact to 4=severe cognitive/emotional impact). A higher score indicated more severe cognitive/emotional impact. Per protocol, change from baseline in the cognitive/emotional impacts domain score at Week 24 was reported for DBPC period. The analysis population included all randomized participants who received at least one dose of study treatment and who had a baseline cognitive/emotional impacts domain score.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Sotatercept plus background PAH therapy (DBPC period) Placebo plus background PAH therapy (DBPC period)
    Number of subjects analysed
    163
    160
    Units: Score on a scale
        median (full range (min-max))
    0.00 (0.00 to 0.00)
    0.000007 (0.00 to 0.0006)
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Sotatercept plus background PAH therapy (DBPC period) v Placebo plus background PAH therapy (DBPC period)
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.156 [14]
    Method
    		 ARSW test
    Parameter type
    		 Treatment difference
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.399
         upper limit
    		 0.084
    Notes
    [14] - A 2-sided p-value was calculated using ARSW test with WHO FC II/III and background PAH therapy as strata.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 19 months
    Adverse event reporting additional description
    All-cause mortality was reported on all randomized participants. Serious and non-serious adverse events were reported on all randomized participants who received at least one dose of study treatment. Mortality and safety were reported separately for the DBPC and LTDB periods.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Sotatercept Plus Background PAH Therapy (DBPC Period)
    Reporting group description
    		 Participants received a starting dose of sotatercept 0.3 mg/kg titrated up to 0.7mg/kg by subcutaneous (SC) injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks.

    Reporting group title
    Placebo Plus Background PAH Therapy (LTDB Period)
    Reporting group description
    		 Participants received dose matched placebo SC injection every 21 days plus background PAH therapy during the LTDB period for up to approximately 72 weeks.

    Reporting group title
    Sotatercept Plus Background PAH Therapy (LTDB Period)
    Reporting group description
    		 Participants received sotatercept dose titrated up to 0.7mg/kg SC injection every 21 days plus background PAH therapy during the LTDB period for up to approximately 72 weeks.

    Reporting group title
    Placebo Plus Background PAH Therapy (DBPC Period)
    Reporting group description
    		 Participants received dose matched placebo SC injection every 21 days plus background PAH therapy during the DBPC period for up to approximately 24 weeks.

    Serious adverse events
    		 Sotatercept Plus Background PAH Therapy (DBPC Period) Placebo Plus Background PAH Therapy (LTDB Period) Sotatercept Plus Background PAH Therapy (LTDB Period) Placebo Plus Background PAH Therapy (DBPC Period)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 163 (14.11%)
    14 / 142 (9.86%)
    26 / 158 (16.46%)
    36 / 160 (22.50%)
         number of deaths (all causes)
    0
    1
    2
    6
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 142 (0.70%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian neoplasm
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism venous
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Complication associated with device
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 142 (0.70%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device occlusion
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    2 / 158 (1.27%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary artery aneurysm
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 163 (0.61%)
    2 / 142 (1.41%)
    0 / 158 (0.00%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Interstitial lung disease
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 163 (1.23%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 142 (0.70%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 142 (0.70%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 142 (0.70%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 142 (0.70%)
    0 / 158 (0.00%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device physical property issue
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device leakage
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 142 (0.70%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial necrosis marker increased
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Neck injury
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 163 (1.23%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Atrial flutter
         subjects affected / exposed
    2 / 163 (1.23%)
    1 / 142 (0.70%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 142 (0.70%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 142 (0.70%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 142 (0.70%)
    0 / 158 (0.00%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Palpitations
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 142 (0.70%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 142 (0.70%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroduodenal ulcer
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    2 / 158 (1.27%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 163 (0.61%)
    1 / 142 (0.70%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Sjogren's syndrome
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Catheter site infection
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    2 / 158 (1.27%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 142 (0.70%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    2 / 158 (1.27%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    2 / 158 (1.27%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-acute COVID-19 syndrome
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Sepsis syndrome
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    1 / 158 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid retention
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    0 / 163 (0.00%)
    2 / 142 (1.41%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 142 (0.00%)
    0 / 158 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 142 (0.70%)
    0 / 158 (0.00%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sotatercept Plus Background PAH Therapy (DBPC Period) Placebo Plus Background PAH Therapy (LTDB Period) Sotatercept Plus Background PAH Therapy (LTDB Period) Placebo Plus Background PAH Therapy (DBPC Period)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    111 / 163 (68.10%)
    50 / 142 (35.21%)
    82 / 158 (51.90%)
    88 / 160 (55.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    9 / 163 (5.52%)
    2 / 142 (1.41%)
    2 / 158 (1.27%)
    3 / 160 (1.88%)
         occurrences all number
    10
    2
    2
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    17 / 163 (10.43%)
    7 / 142 (4.93%)
    6 / 158 (3.80%)
    3 / 160 (1.88%)
         occurrences all number
    20
    7
    6
    4
    Headache
         subjects affected / exposed
    33 / 163 (20.25%)
    6 / 142 (4.23%)
    9 / 158 (5.70%)
    24 / 160 (15.00%)
         occurrences all number
    41
    7
    9
    30
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    8 / 163 (4.91%)
    0 / 142 (0.00%)
    8 / 158 (5.06%)
    3 / 160 (1.88%)
         occurrences all number
    9
    0
    9
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    17 / 163 (10.43%)
    4 / 142 (2.82%)
    10 / 158 (6.33%)
    12 / 160 (7.50%)
         occurrences all number
    20
    4
    12
    12
    Injection site pain
         subjects affected / exposed
    11 / 163 (6.75%)
    1 / 142 (0.70%)
    0 / 158 (0.00%)
    10 / 160 (6.25%)
         occurrences all number
    12
    1
    0
    12
    Oedema peripheral
         subjects affected / exposed
    8 / 163 (4.91%)
    3 / 142 (2.11%)
    6 / 158 (3.80%)
    10 / 160 (6.25%)
         occurrences all number
    10
    3
    7
    10
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    17 / 163 (10.43%)
    3 / 142 (2.11%)
    8 / 158 (5.06%)
    17 / 160 (10.63%)
         occurrences all number
    25
    5
    11
    26
    Diarrhoea
         subjects affected / exposed
    20 / 163 (12.27%)
    3 / 142 (2.11%)
    6 / 158 (3.80%)
    12 / 160 (7.50%)
         occurrences all number
    21
    4
    7
    13
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 163 (1.84%)
    6 / 142 (4.23%)
    2 / 158 (1.27%)
    12 / 160 (7.50%)
         occurrences all number
    4
    7
    2
    15
    Epistaxis
         subjects affected / exposed
    20 / 163 (12.27%)
    1 / 142 (0.70%)
    25 / 158 (15.82%)
    3 / 160 (1.88%)
         occurrences all number
    24
    5
    36
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    9 / 163 (5.52%)
    2 / 142 (1.41%)
    5 / 158 (3.16%)
    4 / 160 (2.50%)
         occurrences all number
    10
    2
    6
    5
    Telangiectasia
         subjects affected / exposed
    17 / 163 (10.43%)
    2 / 142 (1.41%)
    12 / 158 (7.59%)
    5 / 160 (3.13%)
         occurrences all number
    21
    4
    16
    5
    Infections and infestations
    COVID-19
         subjects affected / exposed
    24 / 163 (14.72%)
    21 / 142 (14.79%)
    24 / 158 (15.19%)
    19 / 160 (11.88%)
         occurrences all number
    25
    21
    24
    19
    Nasopharyngitis
         subjects affected / exposed
    7 / 163 (4.29%)
    5 / 142 (3.52%)
    4 / 158 (2.53%)
    9 / 160 (5.63%)
         occurrences all number
    9
    5
    4
    10
    Urinary tract infection
         subjects affected / exposed
    5 / 163 (3.07%)
    3 / 142 (2.11%)
    8 / 158 (5.06%)
    3 / 160 (1.88%)
         occurrences all number
    5
    3
    8
    4
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    9 / 163 (5.52%)
    1 / 142 (0.70%)
    6 / 158 (3.80%)
    5 / 160 (3.13%)
         occurrences all number
    9
    1
    7
    5
    Iron deficiency
         subjects affected / exposed
    2 / 163 (1.23%)
    3 / 142 (2.11%)
    9 / 158 (5.70%)
    7 / 160 (4.38%)
         occurrences all number
    2
    3
    9
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Oct 2021
    The major change for AM1 is to clarify that the Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domains of the PAH-SYMPACT will be evaluated as the secondary endpoints and EQ-5D-5L was removed as the secondary endpoint, removed hematology results requirement prior to study treatment, removed diuretics” from the description of background PAH therapy.06-Oct-2021

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

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