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    Clinical Trial Results:
    A Phase 2 Multicenter, Randomized, Open Label, Multiple Dose Study of Intravenous and Subcutaneous Administration of Sotatercept (ACE-011) in Subjects with End-Stage Kidney Disease on Hemodialysis Switched from Erythropoiesis Stimulating Agents with Staggered Dose Group Escalation in Part 1 Followed by a Parallel Group, Active Controlled Study of Selected Dose(s) and Regimen(s) in Part 2: to Evaluate the Pharmacokinetics, Safety, Tolerability, Efficacy, Dosing Regimen, and Pharmacodynamics of Sotatercept

    Summary
    EudraCT number
    		 2012-003788-23
    Trial protocol
    		 BE   PT   GB   DE   ES  
    Global end of trial date
    22 Aug 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Sep 2017
    First version publication date
    06 Sep 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ACE-011-REN-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01999582
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, United States, 07901
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@celgene.com
    Scientific contact
    Ted Reiss, Celgene Corporation, 01 908-897-6546, treiss@celgene.com
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, United States, 07901
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 888-266-1599, ClinicalTrialDisclosure@celgene.com
    Scientific contact
    Ted Reiss, CVP, Head of I&I Clinical R&D, Celgene Corporation, 01 908-897-6546, TReiss@celgene.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
    08 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Aug 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Part 1 To determine the multiple dose pharmacokinetics, safety, and tolerability of IV and SQ dosing of sotatercept administered at each dose level. Part 2 To determine the safety and efficacy of the selected starting dose(s), route(s) of administration, and dose modification regimen(s) on maintenance of hemoglobin concentrations between baseline and the Evaluation Phase
    Protection of trial subjects
    Patient Confidentiality, Personal Data Protection and Biomarker Consent
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Germany: 19
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    31
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 23 study centers in Belgium, Germany, Portugal, Spain, and the United Kingdom

    Pre-assignment
    Screening details
    		 Subjects with end stage kidney disease (ESKD) on maintenance hemodialysis must have demonstrated a stable hemoglobin (hbg) response to erythropoiesis stimulating agents (ESAs) (hemoglobin ≥ 10 g/dL to ≤ 12 g/dL [≥ 100 g/L to ≤ 120 g/L]) and switched from their ESA to sotatercept.

    Period 1
    Period 1 title
    Overall Study (Up to Visit 14) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection
    Arm description
    		 Subjects received sotatercept at 0.1 mg/kg administered IV every 14 days for up to 8 doses to evaluate the Pharmacokinetic (PK) and safety of IV versus subcutaneous (SQ) dosing of sotatercept.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotatercept
    Investigational medicinal product code
    Other name
    ACE-011
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Sotatercept at 0.1 mg/kg administered IV every 14 days for up to 8 doses. to evaluate the PK and safety of IV versus SQ dosing of sotatercept

    Arm title
    		 Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection
    Arm description
    		 Subjects received sotatercept at 0.13 mg/kg administered SC every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotatercept
    Investigational medicinal product code
    Other name
    ACE-011
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sotatercept at 0.13 mg/kg administered SC every 14 days for up to 8 doses.

    Arm title
    		 Group 2: Sotatercept 0.2 mg/kg IV injection
    Arm description
    		 Subjects received sotatercept at 0.2 mg/kg administered IV every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotatercept
    Investigational medicinal product code
    Other name
    ACE-011
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Sotatercept 0.2 mg/kg administered IV every 14 days for up to 8 doses. to evaluate the PK and safety of IV versus SQ dosing of sotatercept

    Arm title
    		 Group 2: Sotatercept 0.26 mg/kg SC injection
    Arm description
    		 Subjects received sotatercept at 0.26 mg/kg administered SC every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotatercept
    Investigational medicinal product code
    Other name
    ACE-011
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Sotatercept 0.26 mg/kg administered SC every 14 days for up to 8 doses.

    Arm title
    		 Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection
    Arm description
    		 Subjects received sotatercept at a starting dose of 0.1 mg/kg that could be increased up to 0.4 mg/kg administered IV every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotatercept
    Investigational medicinal product code
    Other name
    ACE-011
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Sotatercept dose started at 0.1 mg/kg that could be escalated in 0.1 mg/kg increments up to 0.4 mg/kg administered IV every 14 days for up to 8 doses based on dose escalation rules.

    Arm title
    		 Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection
    Arm description
    		 Subjects received sotatercept at 0.4 mg/kg that could be increased to 0.5 mg/kg administered SC every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotatercept
    Investigational medicinal product code
    Other name
    ACE-011
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sotatercept dose started at 0.4 mg/kg that could be escalated to 0.5 mg/kg based on dose escalation rules and administered SC every 14 days for up to 8 doses.

    Number of subjects in period 1
    		Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection Group 2: Sotatercept 0.2 mg/kg IV injection Group 2: Sotatercept 0.26 mg/kg SC injection Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection
    Started
    7
    7
    9
    9
    12
    6
    Completed
    4
    4
    3
    6
    10
    3
    Not completed
    3
    3
    6
    3
    2
    3
         Consent withdrawn by subject
    -
    -
    -
    1
    -
    -
         Adverse event, non-fatal
    -
    -
    3
    -
    1
    -
         Protocol violation
    -
    -
    -
    -
    -
    1
         Miscellaneous
    1
    -
    3
    1
    1
    2
         Lack of efficacy
    1
    3
    -
    1
    -
    -
         Protocol deviation
    1
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection
    Reporting group description
    		 Subjects received sotatercept at 0.1 mg/kg administered IV every 14 days for up to 8 doses to evaluate the Pharmacokinetic (PK) and safety of IV versus subcutaneous (SQ) dosing of sotatercept.

    Reporting group title
    Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection
    Reporting group description
    		 Subjects received sotatercept at 0.13 mg/kg administered SC every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.

    Reporting group title
    Group 2: Sotatercept 0.2 mg/kg IV injection
    Reporting group description
    		 Subjects received sotatercept at 0.2 mg/kg administered IV every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.

    Reporting group title
    Group 2: Sotatercept 0.26 mg/kg SC injection
    Reporting group description
    		 Subjects received sotatercept at 0.26 mg/kg administered SC every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.

    Reporting group title
    Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection
    Reporting group description
    		 Subjects received sotatercept at a starting dose of 0.1 mg/kg that could be increased up to 0.4 mg/kg administered IV every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.

    Reporting group title
    Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection
    Reporting group description
    		 Subjects received sotatercept at 0.4 mg/kg that could be increased to 0.5 mg/kg administered SC every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.

    Reporting group values
    		 Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection Group 2: Sotatercept 0.2 mg/kg IV injection Group 2: Sotatercept 0.26 mg/kg SC injection Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection Total
    Number of subjects
    		 7 7 9 9 12 6 50
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 5 4 6 4 8 4 31
        From 65-84 years
    		 2 3 3 5 4 2 19
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.1 ( 15.43 ) 62.3 ( 13.03 ) 59.4 ( 15.8 ) 61.9 ( 15.43 ) 61.4 ( 15.68 ) 53.7 ( 15.93 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 3 4 3 5 3 22
        Male
    		 3 4 5 6 7 3 28
    Race
    Units: Subjects
        White
    		 4 5 6 8 11 6 40
        Black or African- American
    		 1 1 1 0 1 0 4
        Asian
    		 2 0 2 1 0 0 5
        American Indian/Alaska Native
    		 0 1 0 0 0 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 1 1 0 0 0 2
        Not Hispanic or Latino
    		 7 6 8 9 12 6 48
    Frequency of dialysis
    Units: Subjects
        Once weekly
    		 0 0 0 0 0 0 0
        Twice weekly
    		 0 0 0 0 1 0 1
        Three times weekly
    		 7 7 8 9 11 6 48
        Four times weekly
    		 0 0 1 0 0 0 1
        Once daily
    		 0 0 0 0 0 0 0
    Duration of dialysis
    Units: minutes
        arithmetic mean (standard deviation)
    		 284.3 ( 26.99 ) 262.1 ( 27.97 ) 241.6 ( 33.34 ) 255.8 ( 25.67 ) 250.7 ( 18.09 ) 259 ( 23.45 ) -

    End points

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    End points reporting groups
    Reporting group title
    Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection
    Reporting group description
    		 Subjects received sotatercept at 0.1 mg/kg administered IV every 14 days for up to 8 doses to evaluate the Pharmacokinetic (PK) and safety of IV versus subcutaneous (SQ) dosing of sotatercept.

    Reporting group title
    Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection
    Reporting group description
    		 Subjects received sotatercept at 0.13 mg/kg administered SC every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.

    Reporting group title
    Group 2: Sotatercept 0.2 mg/kg IV injection
    Reporting group description
    		 Subjects received sotatercept at 0.2 mg/kg administered IV every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.

    Reporting group title
    Group 2: Sotatercept 0.26 mg/kg SC injection
    Reporting group description
    		 Subjects received sotatercept at 0.26 mg/kg administered SC every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.

    Reporting group title
    Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection
    Reporting group description
    		 Subjects received sotatercept at a starting dose of 0.1 mg/kg that could be increased up to 0.4 mg/kg administered IV every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.

    Reporting group title
    Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection
    Reporting group description
    		 Subjects received sotatercept at 0.4 mg/kg that could be increased to 0.5 mg/kg administered SC every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.

    Primary: Area Under the Serum Concentration-Time Curve Over Dosing Interval (AUC14d) (14 days)

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    End point title
    		 Area Under the Serum Concentration-Time Curve Over Dosing Interval (AUC14d) (14 days) [1]
    End point description
    Area Under the plasma concentration-time curve Over 14-day dosing interval (AUC14) for Sotatercept., The PK population included all subjects in the safety population with at least one non-missing plasma concentration data. All analyses of PK data were based on the PK population and subjects were analyzed according to the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Day 1 predose and postdose at 5 min, 4 hours, 3, 7 and dose 2 pre-dose.
    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: Descriptive statistics (i.e., number of subjects, mean, SD, geometric mean, coefficient of variation (CV%), median, minimum, and maximum) were used to summarize PK parameters for each dose group for PK population. Pharmacokinetic exposure parameters were not estimated for subjects with inadequate PK profiles for 14 days or 28 days or for subjects with dose delays or modifications between Doses 1 and 2.
    End point values
    		 Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection Group 2: Sotatercept 0.2 mg/kg IV injection Group 2: Sotatercept 0.26 mg/kg SC injection Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection
    Number of subjects analysed
    4
    3
    7
    6
    7
    5
    Units: day*ng/mL
        arithmetic mean (standard deviation)
    15204.31 ( 7096.55 )
    11269.14 ( 1839.92 )
    28647.03 ( 10332.19 )
    10327.98 ( 8065.12 )
    15886.83 ( 4212.12 )
    21982.9 ( 5125.4 )
    No statistical analyses for this end point

    Primary: Area under the serum concentration- time curve over from Day 1 to Day 28 (AUC28d)

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    End point title
    		 Area under the serum concentration- time curve over from Day 1 to Day 28 (AUC28d) [2]
    End point description
    Area under the plasma concentration-time curve Over 28-day dosing interval (AUC28d). The PK population included all subjects in the safety population with at least one non-missing plasma concentration data. All analyses of PK data were based on the PK population and subjects were analyzed according to the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Doses 1-2: predose and postdose (5 min, 4 hours, 3 and 7 days after each dose) and dose 3 predose.
    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: Descriptive statistics (i.e., number of subjects, mean, SD, geometric mean, coefficient of variation (CV%), median, minimum, and maximum) were used to summarize PK parameters for each dose group for PK population. Pharmacokinetic exposure parameters were not estimated for subjects with inadequate PK profiles for 14 days or 28 days or for subjects with dose delays or modifications between Doses 1 and 2.
    End point values
    		 Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection Group 2: Sotatercept 0.2 mg/kg IV injection Group 2: Sotatercept 0.26 mg/kg SC injection Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection
    Number of subjects analysed
    4
    3
    3
    4
    5
    2
    Units: day*ng/mL
        arithmetic mean (standard deviation)
    38361.5 ( 8589.34 )
    41500.36 ( 13647.28 )
    94106.54 ( 37204.17 )
    36065.09 ( 22817 )
    33173.4 ( 8709.16 )
    60497.8 ( 14623.13 )
    No statistical analyses for this end point

    Primary: Maximum Observed Serum Concentration Obtained From the First Dose (Cmax14d)

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    End point title
    		 Maximum Observed Serum Concentration Obtained From the First Dose (Cmax14d) [3]
    End point description
    Maximum observed serum concentration (Cmax14d) of sotatercept, obtained directly from the observed concentration-time data. The PK population included all subjects in the safety population with at least one non-missing plasma concentration data. All analyses of PK data were based on the PK population and subjects were analyzed according to the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Dose 1: predose and postdose at 5 min, 4 hours, 3 and 7 days and dose 2 predose.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics (i.e., number of subjects, mean, SD, geometric mean, coefficient of variation (CV%), median, minimum, and maximum) were used to summarize PK parameters for each dose group for PK population. Pharmacokinetic exposure parameters were not estimated for subjects with inadequate PK profiles for 14 days or 28 days or for subjects with dose delays or modifications between Doses 1 and 2.
    End point values
    		 Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection Group 2: Sotatercept 0.2 mg/kg IV injection Group 2: Sotatercept 0.26 mg/kg SC injection Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection
    Number of subjects analysed
    4
    3
    8
    6
    7
    5
    Units: ng/mL
        arithmetic mean (standard deviation)
    2567.6 ( 1093.73 )
    1024.27 ( 145.8 )
    4623.61 ( 1620.66 )
    963.05 ( 659.65 )
    3155.53 ( 1861.07 )
    1993.58 ( 375.54 )
    No statistical analyses for this end point

    Primary: Maximum Observed Serum Concentration (Cmax28d) Obtained From the Combined First 2 Doses

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    End point title
    		 Maximum Observed Serum Concentration (Cmax28d) Obtained From the Combined First 2 Doses [4]
    End point description
    Maximum observed serum concentration (Cmax28d) of sotatercept, obtained directly from the observed concentration-time data combining the profiles following the first two doses. The PK population included all subjects in the safety population with at least one non-missing plasma concentration data. All analyses of PK data were based on the PK population and subjects were analyzed according to the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Doses 1-2 predose and postdose at 5 min, 4 hours, 3 and 7 days after each dose and dose 3 predose.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics (i.e., number of subjects, mean, SD, geometric mean, coefficient of variation (CV%), median, minimum, and maximum) were used to summarize PK parameters for each dose group for PK population. Pharmacokinetic exposure parameters were not estimated for subjects with inadequate PK profiles for 14 days or 28 days or for subjects with dose delays or modifications between Doses 1 and 2.
    End point values
    		 Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection Group 2: Sotatercept 0.2 mg/kg IV injection Group 2: Sotatercept 0.26 mg/kg SC injection Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection
    Number of subjects analysed
    4
    3
    3
    4
    5
    2
    Units: mg/mL
        arithmetic mean (standard deviation)
    3557.93 ( 699.19 )
    3868.83 ( 3614.89 )
    8613.67 ( 3559.69 )
    1967.55 ( 1128.69 )
    3501.54 ( 2144.15 )
    3161.6 ( 788.14 )
    No statistical analyses for this end point

    Primary: Time to Reach Maximum Observed Serum Concentration (Tmax)

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    End point title
    		 Time to Reach Maximum Observed Serum Concentration (Tmax) [5]
    End point description
    Time to maximum serum concentration (Tmax) of sotatercept, obtained directly from the observed concentration-time data. The PK population included all subjects in the safety population with at least one non-missing plasma concentration data. All analyses of PK data were based on the PK population and subjects were analyzed according to the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Doses 1-2 predose and postdose at 4 hours, 3, and 7 days after each dose and dose 3 predose.
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics (i.e., number of subjects, mean, SD, geometric mean, coefficient of variation (CV%), median, minimum, and maximum) were used to summarize PK parameters for each dose group for PK population. Pharmacokinetic exposure parameters were not estimated for subjects with inadequate PK profiles for 14 days or 28 days or for subjects with dose delays or modifications between Doses 1 and 2.
    End point values
    		 Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection Group 2: Sotatercept 0.2 mg/kg IV injection Group 2: Sotatercept 0.26 mg/kg SC injection Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection
    Number of subjects analysed
    4
    3
    3
    4
    5
    2
    Units: days
        median (full range (min-max))
    14.09 (14.01 to 16)
    21.01 (16.16 to 27.98)
    14.02 (13.99 to 16.01)
    18.51 (15.99 to 21.02)
    0.1688 (0.0035 to 15.99)
    21.06 (20.99 to 21.13)
    No statistical analyses for this end point

    Primary: Estimate of Terminal Elimination Half-Life in Serum at Final Dose Only (t1/2)

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    End point title
    		 Estimate of Terminal Elimination Half-Life in Serum at Final Dose Only (t1/2) [6]
    End point description
    Terminal elimination half-life (T1/2). The PK population included all subjects in the safety population with at least one non-missing plasma concentration data. All analyses of PK data were based on the PK population and subjects were analyzed according to the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Last dose (Day 99), predose and 4 hours and 3, 7, 14, 21, 28, 56, 84 and 112 days after the final dose.
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics (i.e., number of subjects, mean, SD, geometric mean, coefficient of variation (CV%), median, minimum, and maximum) were used to summarize PK parameters for each dose group for PK population. Pharmacokinetic exposure parameters were not estimated for subjects with inadequate PK profiles for 14 days or 28 days or for subjects with dose delays or modifications between Doses 1 and 2.
    End point values
    		 Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection Group 2: Sotatercept 0.2 mg/kg IV injection Group 2: Sotatercept 0.26 mg/kg SC injection Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection
    Number of subjects analysed
    6
    4
    6
    8
    9
    4
    Units: days
        arithmetic mean (standard deviation)
    17.6 ( 4.631 )
    25.87 ( 7.127 )
    21.76 ( 3.941 )
    21.03 ( 5.4 )
    22.46 ( 5.342 )
    20.39 ( 5.3 )
    No statistical analyses for this end point

    Primary: Lambda (ʎz): Apparent Terminal Rate Constant (at Final Dose Only)

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    End point title
    		 Lambda (ʎz): Apparent Terminal Rate Constant (at Final Dose Only) [7]
    End point description
    Lambda, apparent terminal rate constant (final dose only). The PK population included all subjects in the safety population with at least one non-missing plasma concentration data. All analysis of PK data were based on the PK population and subjects were analyzed according to the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Last dose, predose and 4 hours and 3, 7, 14, 21, 28, 56, 84 and 112 days after the final dose.
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics (i.e., number of subjects, mean, SD, geometric mean, coefficient of variation (CV%), median, minimum, and maximum) were used to summarize PK parameters for each dose group for PK population. Pharmacokinetic exposure parameters were not estimated for subjects with inadequate PK profiles for 14 days or 28 days or for subjects with dose delays or modifications between Doses 1 and 2.
    End point values
    		 Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection Group 2: Sotatercept 0.2 mg/kg IV injection Group 2: Sotatercept 0.26 mg/kg SC injection Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection
    Number of subjects analysed
    6
    4
    6
    8
    4
    4
    Units: 1/day
        arithmetic mean (standard deviation)
    0.0414 ( 0.0094 )
    0.0282 ( 0.0071 )
    0.0328 ( 0.0063 )
    0.0346 ( 0.0078 )
    0.0326 ( 0.0085 )
    0.0355 ( 0.0077 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Mean Hemoglobin ≥ 100 g/dL to ≤ 120 g/L Without Rescue Medication

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    End point title
    		 Percentage of Subjects With Mean Hemoglobin ≥ 100 g/dL to ≤ 120 g/L Without Rescue Medication
    End point description
    The percentage of subjects able to maintain a mean hemoglobin concentration ≥ 100 g/dL to ≤ 120 g/L without rescue medication from Visit 14 to Visit 17 (days 99 to 113), defined as the mean of hemoglobin concentrations between Study Day 98 and Study Day 115, inclusive. The Full Analysis Set (FAS) includes all randomized subjects who receive at least one dose of IP.
    End point type
    Secondary
    End point timeframe
    Baseline and visit 14 to Visit 17 (days 99 to 113)
    End point values
    		 Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection Group 2: Sotatercept 0.2 mg/kg IV injection Group 2: Sotatercept 0.26 mg/kg SC injection Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection
    Number of subjects analysed
    7
    7
    9
    9
    12
    6
    Units: percentage of subjects
        number (not applicable)
    42.9
    42.9
    11.1
    33.3
    25
    50
    No statistical analyses for this end point

    Secondary: Change from Baseline in Mean Hemoglobin Concentration for Visit 14 to 17 (All Subjects Regardless of Rescue)

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    End point title
    		 Change from Baseline in Mean Hemoglobin Concentration for Visit 14 to 17 (All Subjects Regardless of Rescue)
    End point description
    Baseline hemoglobin value was defined as the mean of three consecutive hemoglobin concentrations with the last hemoglobin concentration measured between the 7th day prior to randomization and the day of randomization, if available. Visit 14 to Visit 17 hemoglobin value was defined as mean of hemoglobin concentrations between Study Day 98 and Study Day 115, inclusive. Includes subjects with non-missing baseline and Day 98 to Day 115 hemoglobin values. Full Analysis Set Population includes all randomized subjects who received at least one dose of Investigational Product.
    End point type
    Secondary
    End point timeframe
    Baseline and Visit 14 to Visit 17 (days 99 to 113)
    End point values
    		 Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection Group 2: Sotatercept 0.2 mg/kg IV injection Group 2: Sotatercept 0.26 mg/kg SC injection Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection
    Number of subjects analysed
    7
    5
    5
    7
    9
    4
    Units: g/dL
        arithmetic mean (standard deviation)
    -6.9 ( 11.61 )
    -2.7 ( 6.47 )
    -2.1 ( 12.23 )
    -0.8 ( 10.03 )
    -9.9 ( 9.3 )
    -6.4 ( 12.6 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Mean Hemoglobin Concentration for Visit 14 to 17 (Subjects Not Rescued Prior to Day 115)

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    End point title
    		 Change from Baseline in Mean Hemoglobin Concentration for Visit 14 to 17 (Subjects Not Rescued Prior to Day 115)
    End point description
    Baseline hemoglobin value was defined as the mean of three consecutive hemoglobin concentrations with the last hemoglobin concentration measured between the 7th day prior to randomization and the day of randomization, if available. Visit 14 to Visit 17 hemoglobin value was defined as mean of hemoglobin concentrations between Study Day 98 and Study Day 115, inclusive. Includes subjects with non-missing baseline and Day 98 to Day 115 hemoglobin values. Full Analysis Set Population includes all randomized subjects who received at least one dose of Investigational Product.
    End point type
    Secondary
    End point timeframe
    Baseline and Visit 14 to Visit 17 (days 99 to 113)
    End point values
    		 Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection Group 2: Sotatercept 0.2 mg/kg IV injection Group 2: Sotatercept 0.26 mg/kg SC injection Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection
    Number of subjects analysed
    3
    4
    2
    6
    6
    3
    Units: g/L)
        arithmetic mean (standard deviation)
    -7 ( 6.24 )
    -3.6 ( 7.08 )
    -0.3 ( 15.2 )
    0.5 ( 10.28 )
    -13 ( 10.07 )
    -1 ( 8.05 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Adverse Events (AEs)

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    End point title
    		 Number of Participants With Adverse Events (AEs)
    End point description
    Treatment-emergent adverse event (TEAE) was defined as an adverse event with start date on or after date of first dose of study drug. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject’s health, including laboratory test values, regardless of etiology. A serious adverse event is defined as any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. Severity and intensity was assessed using the following grading scale: Mild, Moderate and Severe (could be non-serious or serious).
    End point type
    Secondary
    End point timeframe
    From date of first dose of investigational product to 112 days after the last dose of investigational product or until the last study visit, whichever period was longer. The maximum duration for any IV or SC dose was 114 days.
    End point values
    		 Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) injection Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) injection Group 2: Sotatercept 0.2 mg/kg IV injection Group 2: Sotatercept 0.26 mg/kg SC injection Group 3: Sotatercept 0.1 – 0.4 mg/kg IV injection Group 3: Sotatercept 0.4 – 0.5 mg/kg SC injection
    Number of subjects analysed
    7
    7
    9
    9
    12
    6
    Units: subjects
        Any TEAE
    7
    3
    9
    6
    10
    6
        Any treatment related TEAE
    1
    1
    1
    0
    0
    1
        Any serious TEAE
    3
    0
    3
    1
    3
    3
        Any treatment-related serious TEAE
    0
    0
    0
    0
    0
    0
        Any TEAE leading to study drug discontinuation
    0
    0
    3
    0
    1
    0
        Any severe TEAE
    0
    0
    2
    0
    1
    2
        Any TEAE leading to death
    0
    0
    0
    0
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of IP up to final/early termination visit or 112 +/- 3 days after the last dose of sotatercept. The maximum duration of exposure to IP for any IV/SC dose was 114 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Sotatercept 0.1 mg/kg IV
    Reporting group description
    		 Subjects received sotatercept at 0.1 mg/kg administered IV every 14 days for up to 8 doses to evaluate the Pharmacokinetic (PK) and safety of IV versus subcutaneous (SC) dosing of sotatercept.

    Reporting group title
    Sotatercept 0.13 mg/kg SC
    Reporting group description
    		 Subjects received sotatercept at 0.13 mg/kg administered SC every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.

    Reporting group title
    Sotatercept 0.2 mg/kg IV
    Reporting group description
    		 Subjects received sotatercept at 0.2 mg/kg administered IV every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.

    Reporting group title
    Sotatercept 0.26 mg/kg SC
    Reporting group description
    		 Subjects received sotatercept at 0.26 mg/kg administered SC every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.

    Reporting group title
    Sotatercept 0.1 to 0.4 mg/kg IV
    Reporting group description
    		 Subjects received sotatercept at a starting dose of 0.1 mg/kg that could be increased up to a dose of 0.4 mg/kg administered IV every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.

    Reporting group title
    Sotatercept 0.4 to 0.5 mg/kg SC
    Reporting group description
    		 Subjects received sotatercept at 0.4 mg/kg that could be increased up to a dose of 0.5 mg/kg administered SC every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.

    Serious adverse events
    		 Sotatercept 0.1 mg/kg IV Sotatercept 0.13 mg/kg SC Sotatercept 0.2 mg/kg IV Sotatercept 0.26 mg/kg SC Sotatercept 0.1 to 0.4 mg/kg IV Sotatercept 0.4 to 0.5 mg/kg SC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 7 (0.00%)
    3 / 9 (33.33%)
    1 / 9 (11.11%)
    3 / 12 (25.00%)
    3 / 6 (50.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Arteriovenous graft site stenosis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shunt thrombosis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular access malfunction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Chronic gastritis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal angiodysplasia haemorrhagic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sotatercept 0.1 mg/kg IV Sotatercept 0.13 mg/kg SC Sotatercept 0.2 mg/kg IV Sotatercept 0.26 mg/kg SC Sotatercept 0.1 to 0.4 mg/kg IV Sotatercept 0.4 to 0.5 mg/kg SC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    3 / 7 (42.86%)
    9 / 9 (100.00%)
    6 / 9 (66.67%)
    9 / 12 (75.00%)
    6 / 6 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Juvenile melanoma benign
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Vascular disorders
    Extravasation blood
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Extremity necrosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Haematoma
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    2 / 9 (22.22%)
    2 / 12 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    1
    0
    2
    2
    2
    2
    Hypotension
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    3
    1
    0
    0
    Pallor
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Face oedema
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    0
    0
    2
    Pyrexia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    1
    0
    0
    0
    Reproductive system and breast disorders
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    Nasal obstruction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Respiratory acidosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Sleep disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Investigations
    Cardioactive drug level increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Arteriovenous fistula site complication
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 7 (28.57%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    3
    0
    0
    Arteriovenous fistula site haematoma
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    Arteriovenous fistula site haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Fall
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Foreign body
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Haemodialysis-induced symptom
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    Hand fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Post-traumatic pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Procedural hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Procedural pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Wound secretion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Nervous system disorders
    Diabetic neuropathy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    3 / 6 (50.00%)
         occurrences all number
    0
    0
    1
    0
    2
    3
    Ischaemic stroke
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Eye disorders
    Amaurosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Amaurosis fugax
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Choroidal effusion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Chronic gastritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    0
    1
    0
    1
    Duodenal ulcer
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Intra-abdominal haematoma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    Oesophagitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    5
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus generalised
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    1
    0
    0
    0
    Renal colic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Renal cyst
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hyperparathyroidism secondary
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    3 / 9 (33.33%)
    0 / 12 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    0
    3
    0
    6
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    Tendonitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Cellulitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    1
    1
    0
    0
    2
    Localised infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    Metabolism and nutrition disorders
    Calciphylaxis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Folate deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hyperphosphataemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Sep 2013
    1. Changed Part 1 interim analysis trigger to occur after the 6th subject, instead of 3rd subject, had 14 days follow up after the 3rd IV or SQ dose in each arm. 2. Removed the dose group discontinuation rule for inadequate Hgb response (defined as Hgb concentration < 9.5 g/dL or a > 1 g/L decrease from baseline, 14 days after the 3rd IV or SQ dose in 2 of 3 subjects in either arm). 3. Added new predefined safety criteria for closure of an IV or SQ arm to further enrollment, with discontinuation of sotatercept in each arm if the following were met in 4 of 6 subjects in each arm, prior to receiving rescue therapy: • Hgb discontinuation rule for re-dosing • BP discontinuation rule for re-dosing • SAE considered related to sotatercept 4. Modification to include a threshold BP rule for discontinuation of IP if the pre or postdose mean home systolic BP was > 200 mm Hg or the mean pre or postdose home diastolic BP was > 110 mm Hg at any time during the study. 5. Clarification was provided for reassessment of the mean predose home BP measurements if the BP stopping rule was achieved (but not above the threshold BP [systolic BP > 200 mm Hg and diastolic BP > 100 mm Hg]). 6. The postdose home BP assessment was extended to a 2-day interval, with a minimum of 1 set of 3 measurements after waking and 1 set of 3 measurements before bed required for an adequate sample. 7. Clarification on the identification of AEs of special interest for discontinuation by relating it to the Reference Safety Information in the Sotatercept Investigator’s Brochure which includes increases in Hgb, hematocrit, red blood cells and BP. 8. Information summarizing the frequency of hypersensitivity reactions in the product labels of several Fc fusion protein therapeutics and rituximab; recommendations for handling of hypersensitivity reactions from these labels was also added 9. Free testosterone and estradiol and uncertainties concerning the IPs action on fertility were added to the protocol
    17 Dec 2014
    1. The study design for Part 1, Dose Group 3 was modified to an intrasubject dose escalation design to accommodate an apparent change in Hb response over time, due to an underlying ESA effect washout. Intrasubject dose escalation was implemented in response to subjects’ individual Hb levels both in the IV and SC arms. 2. Dose escalation in Part 1, Dose Group 3 was allowed in increments of 0.1 mg/kg until reaching 0.4 mg/kg every 14 days for the IV arm and 0.5 mg/kg every 14 days for the SC arm. 3. New dose escalation rules were added for both the IV and SQ arms and one of the dose-holding rules was modified to include an absolute Hb level of > 11 g/dL (> 110 g/L) in addition to the increase in Hb of ≥ 1 g/dL (≥ 10 g/L). 4. Sample size was increased to 12 to 18 subjects in the IV arm of Part 1, Dose Group 3 and the randomization was accordingly changed to 2:1, IV versus SC. 5. The ESA-free phase was increased to 10 days for subjects who were on darbepoetin administered by SQ route before entering the study. 6. A mandatory testing for Hb levels by central laboratory method was required for the 3 values of predialysis Hb concentrations for calculation of mean Hb concentration during the screening period. In addition, the predialysis Hb value for dosing eligibility was required by both central laboratory and local methods. 7. A clarification was added for long-term evaluation of anti-sotatercept antibodies based on the last available anti-sotatercept antibody positive result at the time of Final/Early Termination Visit, instead of the sample collected at the Final/Early Termination Visit.

    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.
    Due to a shift in the clinical development strategy for the renal sotatercept program, Part 2 of the study was not conducted; Part 2 objectives were not assessed and none of the statistical analyses in Part 2 were conducted; no safety concerns.
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