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    Clinical Trial Results:
    Early Treatment of Borderline Pulmonary Arterial Hypertension Associated with Systemic Sclerosis (SSc-APAH)

    Summary
    EudraCT number
    		 2014-001882-28
    Trial protocol
    		 DE  
    Global end of trial date
    21 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Apr 2020
    First version publication date
    08 Apr 2020
    Other versions
    Summary report(s)
    		 Clinical Study Report

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2014-05ED
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02290613
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Thoraxklinik Heidelberg gGmbH
    Sponsor organisation address
    Röntgenstraße 1, Heidelberg, Germany,
    Public contact
    Director of the clinic, Thoraxklinik am Universitätsklinikum Heidelberg, +49 6221 396 2100,
    Scientific contact
    Director of the clinic, Thoraxklinik am Universitätsklinikum Heidelberg, +49 6221 396 2100,
    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
    21 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determine whether mPAP of SSc patients with borderline - PAH (mPAP 21 24 mmHg, TPG >11 mmHg) can be reduced by 15% following treatment with ambrisentan 10 mg/die (initiated with 5 mg/die and elevated up to 10 mg/die) over 6 months compared to baseline and placebo.
    Protection of trial subjects
    Annual development safety update reports were submitted to the Ethics committee. Patient safety was ensured by regular safety assessments. In case of clinical Deterioration, measures and Treatment according to clinical routine were taken. Serious adverse Events (SAEs) were described in Detail including severity, expectedness and relation to study drug. In case the investigator who primarily reported the SAE classified the SAE as ‘suspected’ (i.e. either definitely or probable or possible related to the IMP or not assessable) and the SAE was unexpected, a drug safety officer as second Assessor was asked to classify the SAE. All SUSARs were subject to an expedited reporting to the responsible ethics committee(s), the competent higher federal authority, i.e. Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), and to all participating investigators. No SUSARs occurred during the study. Trial findings stored on a computer were stored in accordance with local data protection law and were handled in strictest confidence. For protection of these data, organizational procedures were implemented to prevent distribution of data to unauthorized persons. The appropriate regulations of local data legislation were fulfilled in its entirety.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Sep 2014
    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
    Germany: 38
    Worldwide total number of subjects
    38
    EEA total number of subjects
    38
    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)
    32
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients from the in- and outpatient clinic were recruited. In patients who already underwent a screening with right heart catheterization assessment due to clinical routine within the preceding 6 months, this assessment served as baseline.

    Pre-assignment
    Screening details
    		 Patients were screened by clinical examinations and right heart catheterization. If patients were eligible for the study, the baseline assessment was performed within 28 days from Screening.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Randomization to one of the groups was performed by block randomization. Randomization lists were created by the data management using a computer to generate random numbers. Medication was packed with sequential patient numbers. The randomization list were kept in safe and confidential custody. Emergency envelopes were collected at the end of the Trial by the Trial Monitor and were only to be opened in case of emergency.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ambrisentan
    Arm description
    		 Ambrisentan once daily starting at 5 mg/die in the beginning of the study. Dosage was up-titrated to 10 mg/die after 1-4 weeks according to the physician’s and the patient’s estimation. Study medication was provided orally with or without food. Treatment effect was controlled at each study visit and the dose was adapted. The patient took one or two tablets of ambrisentan 5 mg once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ambrisentan
    Investigational medicinal product code
    Other name
    Volibris
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Titration As to common practice of the clinic, the patient adapted the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needed to decide, based on the patient’s well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) were documented. Maximum dose allowed: not to exceed 10 mg/die. Administration Ambrisentan and placebo was administered orally with or without food intake.

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablets with the same treatment regimen (once daily) as the verum therapy were provided. One pill a day were given. Treatment effect was controlled at each study visit and the sham dose was adapted. The patient took one or two tablets once daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sham Titration in accordance with the protocol with 1 tablet at the beginning and up to 2 tablets after up-titration (4 weeks) with regard to 5 to 10 mg in the Intervention Group.

    Number of subjects in period 1
    		ambrisentan Placebo
    Started
    19
    19
    Completed
    19
    19
    Period 2
    Period 2 title
    6 months
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ambrisentan
    Arm description
    		 Ambrisentan once daily starting at 5 mg/die in the beginning of the study. Dosage was up-titrated to 10 mg/die after 1-4 weeks according to the physician’s and the patient’s estimation. Study medication was provided orally with or without food. Treatment effect was controlled at each study visit and the dose was adapted. The patient took one or two tablets of ambrisentan 5 mg once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ambrisentan
    Investigational medicinal product code
    Other name
    Volibris
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Titration As to common practice of the clinic, the patient adapted the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needed to decide, based on the patient’s well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) were documented. Maximum dose allowed: not to exceed 10 mg/die. Administration Ambrisentan and placebo was administered orally with or without food intake.

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablets with the same treatment regimen (once daily) as the verum therapy were provided. One pill a day were given. Treatment effect was controlled at each study visit and the sham dose was adapted. The patient took one or two tablets once daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sham Titration in accordance with the protocol with 1 tablet at the beginning and up to 2 tablets after up-titration (4 weeks) with regard to 5 to 10 mg in the Intervention Group.

    Number of subjects in period 2
    		ambrisentan Placebo
    Started
    19
    19
    Completed
    17
    15
    Not completed
    2
    4
         Consent withdrawn by subject
    1
    2
         Adverse event, non-fatal
    1
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    ambrisentan
    Reporting group description
    		 Ambrisentan once daily starting at 5 mg/die in the beginning of the study. Dosage was up-titrated to 10 mg/die after 1-4 weeks according to the physician’s and the patient’s estimation. Study medication was provided orally with or without food. Treatment effect was controlled at each study visit and the dose was adapted. The patient took one or two tablets of ambrisentan 5 mg once daily.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets with the same treatment regimen (once daily) as the verum therapy were provided. One pill a day were given. Treatment effect was controlled at each study visit and the sham dose was adapted. The patient took one or two tablets once daily.

    Reporting group values
    		 ambrisentan Placebo Total
    Number of subjects
    		 19 19 38
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.79 ± 10.75 54.89 ± 11.23 -
    Gender categorical
    Units: Subjects
        Female
    		 16 14 30
        Male
    		 3 5 8
    WHO functional class
    WHO functional classification I : no symptoms II: no symptoms at rest but during normal activity (climbing stairs), slight Limitation of normal activity III: no symptoms at rest but during normal activity, marked limitation of normal activity IV: symptoms at rest and during any activity
    Units: Subjects
        II
    		 17 15 32
        III
    		 2 4 6
    Systemic sclerosis subgroup
    Units: Subjects
        diffuse
    		 4 11 15
        limited
    		 15 8 23
    Hemodynamic characteristic according to inclusion criteria
    Units: Subjects
        mPAP rest 21-24mmHg, mPAP exercise >30mmHg
    		 10 12 22
        mPAP rest 21-24mmHg, mPAP exercise ≤30mmHg
    		 1 3 4
        mPAP rest <21mmHg, mPAP exercise >30mmHg
    		 8 4 12
    Mean pulmonary arterial pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 19.84 ± 3.58 21.32 ± 2.43 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 166.05 ± 5.59 166.21 ± 10.19 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 71.45 ± 15.83 74.81 ± 17.25 -
    Systolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 116.32 ± 11.53 121.32 ± 14.99 -
    Diastolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 73.68 ± 8.95 73.42 ± 9.14 -
    Heart rate
    Units: beats/min
        arithmetic mean (standard deviation)
    		 73.05 ± 11.12 77.58 ± 9.85 -
    Modified Rodnan Skin score
    Units: points
        arithmetic mean (standard deviation)
    		 11.47 ± 5.71 11.47 ± 5.22 -
    Systemic sclerosis disease duration
    Units: years
        arithmetic mean (standard deviation)
    		 6.63 ± 4.80 13.28 ± 10.85 -
    Pulmonary arterial wedge pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 9.42 ± 2.32 9.58 ± 2.97 -
    Cardiac Output
    Units: l/min
        arithmetic mean (standard deviation)
    		 5.04 ± 1.26 5.66 ± 1.48 -
    Cardiac Index
    Units: l/min/m2
        arithmetic mean (standard deviation)
    		 2.84 ± 0.64 3.20 ± 0.85 -
    SvO2
    Units: percent
        arithmetic mean (standard deviation)
    		 73.13 ± 4.60 73.94 ± 8.58 -
    Pulmonary vascular resistance
    Units: Wood Units
        arithmetic mean (standard deviation)
    		 2.22 ± 0.93 2.09 ± 0.61 -
    mean pulmonary arterial pressure at peak exercise
    Units: mmHg
        arithmetic mean (standard deviation)
    		 37.78 ± 3.61 36.94 ± 6.08 -
    Pulmonary arterial wedge pressure at peak exercise
    Units: mmHg
        arithmetic mean (standard deviation)
    		 16.78 ± 6.42 15.24 ± 5.43 -
    Cardiac Output at peak exercise
    Units: l/min
        arithmetic mean (standard deviation)
    		 9.67 ± 2.67 11.03 ± 3.62 -
    Cardiac index at peak exercise
    Units: l/min/m2
        arithmetic mean (standard deviation)
    		 5.41 ± 1.32 6.04 ± 1.79 -
    SvO2 at peak exercise
    Units: percent
        arithmetic mean (standard deviation)
    		 42.77 ± 11.56 38.27 ± 6.10 -
    Workload at peak exercise
    Units: watt
        arithmetic mean (standard deviation)
    		 75.00 ± 27.12 75.00 ± 34.23 -
    Heart rate at peak exercise
    Units: beats/min
        arithmetic mean (standard deviation)
    		 111.39 ± 23.06 117.65 ± 21.37 -
    Pulmonary vascular resistance at peak exercise
    Units: Wood Units
        arithmetic mean (standard deviation)
    		 2.29 ± 0.85 2.07 ± 0.61 -
    Total pulmonary resistance
    Units: mmHg*min*l-1
        arithmetic mean (standard deviation)
    		 4.28 ± 1.65 3.65 ± 1.18 -
    6-minute walking distance
    Units: meter
        arithmetic mean (standard deviation)
    		 470.21 ± 77.03 448.11 ± 82.64 -
    Borg dyspnea score
    Units: score
        arithmetic mean (standard deviation)
    		 2.41 ± 1.32 2.93 ± 1.97 -
    Oxygen saturation after 6-minute walking distance
    Units: percent
        arithmetic mean (standard deviation)
    		 91.71 ± 4.79 91.87 ± 4.63 -
    Heart rate after 6-minute walking distance
    Units: beats/minute
        arithmetic mean (standard deviation)
    		 107 ± 19.64 99 ± 21.27 -
    Systolic pulmonary arterial pressure (echocardiography)
    Units: mmHg
        arithmetic mean (standard deviation)
    		 28.58 ± 6.57 29.21 ± 5.16 -
    Right atrial area
    Units: cm2
        arithmetic mean (standard deviation)
    		 11.68 ± 3.28 12.05 ± 4.24 -
    Right ventricular area
    Units: cm2
        arithmetic mean (standard deviation)
    		 14.13 ± 4.74 14.89 ± 4.56 -
    Tricuspid annular plane systolic excursion
    Units: cm
        arithmetic mean (standard deviation)
    		 2.41 ± 0.33 2.50 ± 0.51 -
    Forced Vital Capacity
    Units: percent
        arithmetic mean (standard deviation)
    		 70.51 ± 17.61 69.17 ± 13.72 -
    Forced Expiratory Volume in 1 second
    Units: litre(s)
        arithmetic mean (standard deviation)
    		 2.26 ± 0.63 2.40 ± 0.77 -
    FEV1 % Vital capacity max
    Units: percent
        arithmetic mean (standard deviation)
    		 81.44 ± 15.38 79.31 ± 6.98 -
    PEF
    Units: litre/second
        arithmetic mean (standard deviation)
    		 5.17 ± 1.72 5.46 ± 2.32 -
    Total lung capacity
    Units: litre(s)
        arithmetic mean (standard deviation)
    		 5.08 ± 1.25 4.96 ± 1.07 -
    Residual volume
    Units: litre(s)
        arithmetic mean (standard deviation)
    		 2.18 ± 0.70 1.94 ± 0.55 -
    Diffusion capacity of the lung
    Units: mmol/min/kPa
        arithmetic mean (standard deviation)
    		 5.03 ± 1.33 5.28 ± 1.52 -
    Diffusion capacity of the lung percent predicted
    Units: percent
        arithmetic mean (standard deviation)
    		 84.16 ± 1.89 84.73 ± 2.61 -
    SaO2
    Units: percent
        arithmetic mean (standard deviation)
    		 96.82 ± 0.77 96.13 ± 1.80 -
    PaO2
    Units: mmHg
        arithmetic mean (standard deviation)
    		 81.22 ± 5.91 78.78 ± 9.42 -
    PaCO2
    Units: mmHg
        arithmetic mean (standard deviation)
    		 37.23 ± 2.57 39.01 ± 3.63 -
    Hemoglobin
    Units: g/dl
        arithmetic mean (standard deviation)
    		 13.62 ± 1.13 13.54 ± 1.26 -
    Hematocrit
    Units: 1/l
        arithmetic mean (standard deviation)
    		 0.41 ± 0.03 0.42 ± 0.03 -
    Platelet
    Units: 100/nl
        arithmetic mean (standard deviation)
    		 2.62 ± 0.63 2.53 ± 0.94 -
    Creatinine
    Units: mg/dl
        arithmetic mean (standard deviation)
    		 0.86 ± 0.12 0.83 ± 0.16 -
    Potassium
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 4.20 ± 0.48 4.05 ± 0.38 -
    AST
    Units: U/l
        arithmetic mean (standard deviation)
    		 19.79 ± 7.06 24.11 ± 21.78 -
    ALT
    Units: U/l
        arithmetic mean (standard deviation)
    		 24.68 ± 9.85 29.68 ± 24.93 -
    LDH
    Units: U/l
        arithmetic mean (standard deviation)
    		 197.53 ± 35.59 197.63 ± 54.74 -
    CRP
    Units: mg/l
        arithmetic mean (standard deviation)
    		 5.28 ± 11.60 5.18 ± 5.17 -
    NTproBNP
    Units: pg/ml
        arithmetic mean (standard deviation)
    		 267.83 ± 303.11 123.42 ± 142.96 -
    Physical functioning (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    		 64.21 ± 25.83 50.26 ± 25.95 -
    Physical role functioning (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    		 51.32 ± 41.23 35.53 ± 40.24 -
    Bodily pain (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    		 62.00 ± 29.16 49.79 ± 28.96 -
    General health perception
    Units: score
        arithmetic mean (standard deviation)
    		 54.42 ± 19.47 41.74 ± 13.07 -
    Vitality (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    		 50.53 ± 20.94 42.89 ± 19.32 -
    Social role functioning (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    		 74.47 ± 24.45 58.05 ± 25.99 -
    Emotional role functioning (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    		 63.16 ± 47.02 49.16 ± 46.33 -
    Mental health (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    		 64.42 ± 18.03 59.58 ± 18.85 -
    Physical summation score (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    		 56.47 ± 23.87 43.89 ± 21.26 -
    Mental summation score (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    		 61.42 ± 21.45 50.26 ± 20.70 -
    Subject analysis sets

    Subject analysis set title
    All patients randomised
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Includes all patients that were randomised into the study

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Efficacy analysis set of all patients who completed the study

    Subject analysis set title
    Ambrisentan
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Efficacy analysis of all patients who completed the study

    Subject analysis sets values
    		 All patients randomised Placebo Ambrisentan
    Number of subjects
    38
    15
    17
    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)
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
        Male
    WHO functional class
    WHO functional classification I : no symptoms II: no symptoms at rest but during normal activity (climbing stairs), slight Limitation of normal activity III: no symptoms at rest but during normal activity, marked limitation of normal activity IV: symptoms at rest and during any activity
    Units: Subjects
        II
        III
    Systemic sclerosis subgroup
    Units: Subjects
        diffuse
    15
        limited
    23
    Hemodynamic characteristic according to inclusion criteria
    Units: Subjects
        mPAP rest 21-24mmHg, mPAP exercise >30mmHg
    22
        mPAP rest 21-24mmHg, mPAP exercise ≤30mmHg
    4
        mPAP rest <21mmHg, mPAP exercise >30mmHg
    12
    Mean pulmonary arterial pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    20.58 ± 3.11
    ±
    ±
    Height
    Units: cm
        arithmetic mean (standard deviation)
    166.13 ± 8.11
    ±
    ±
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    73.13 ± 16.42
    ±
    ±
    Systolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    118.82 ± 13.43
    ±
    ±
    Diastolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    73.55 ± 8.92
    ±
    ±
    Heart rate
    Units: beats/min
        arithmetic mean (standard deviation)
    75.32 ± 10.61
    ±
    ±
    Modified Rodnan Skin score
    Units: points
        arithmetic mean (standard deviation)
    11.47 ± 5.40
    ±
    ±
    Systemic sclerosis disease duration
    Units: years
        arithmetic mean (standard deviation)
    9.96 ± 8.93
    ±
    ±
    Pulmonary arterial wedge pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    9.50 ± 2.63
    ±
    ±
    Cardiac Output
    Units: l/min
        arithmetic mean (standard deviation)
    5.35 ± 1.39
    ±
    ±
    Cardiac Index
    Units: l/min/m2
        arithmetic mean (standard deviation)
    3.02 ± 0.76
    ±
    ±
    SvO2
    Units: percent
        arithmetic mean (standard deviation)
    73.53 ± 6.85
    ±
    ±
    Pulmonary vascular resistance
    Units: Wood Units
        arithmetic mean (standard deviation)
    2.16 ± 0.78
    ±
    ±
    mean pulmonary arterial pressure at peak exercise
    Units: mmHg
        arithmetic mean (standard deviation)
    37.37 ± 4.91
    ±
    ±
    Pulmonary arterial wedge pressure at peak exercise
    Units: mmHg
        arithmetic mean (standard deviation)
    16.03 ± 5.92
    ±
    ±
    Cardiac Output at peak exercise
    Units: l/min
        arithmetic mean (standard deviation)
    10.33 ± 3.19
    ±
    ±
    Cardiac index at peak exercise
    Units: l/min/m2
        arithmetic mean (standard deviation)
    5.71 ± 1.58
    ±
    ±
    SvO2 at peak exercise
    Units: percent
        arithmetic mean (standard deviation)
    40.52 ± 9.37
    ±
    ±
    Workload at peak exercise
    Units: watt
        arithmetic mean (standard deviation)
    75.00 ± 30.32
    ±
    ±
    Heart rate at peak exercise
    Units: beats/min
        arithmetic mean (standard deviation)
    114.43 ± 22.15
    ±
    ±
    Pulmonary vascular resistance at peak exercise
    Units: Wood Units
        arithmetic mean (standard deviation)
    2.18 ± 0.74
    ±
    ±
    Total pulmonary resistance
    Units: mmHg*min*l-1
        arithmetic mean (standard deviation)
    3.97 ± 1.46
    ±
    ±
    6-minute walking distance
    Units: meter
        arithmetic mean (standard deviation)
    459.16 ± 79.59
    ±
    ±
    Borg dyspnea score
    Units: score
        arithmetic mean (standard deviation)
    2.67 ± 1.68
    ±
    ±
    Oxygen saturation after 6-minute walking distance
    Units: percent
        arithmetic mean (standard deviation)
    91.78 ± 4.64
    ±
    ±
    Heart rate after 6-minute walking distance
    Units: beats/minute
        arithmetic mean (standard deviation)
    103 ± 20.56
    ±
    ±
    Systolic pulmonary arterial pressure (echocardiography)
    Units: mmHg
        arithmetic mean (standard deviation)
    28.89 ± 5.83
    ±
    ±
    Right atrial area
    Units: cm2
        arithmetic mean (standard deviation)
    11.87 ± 3.74
    ±
    ±
    Right ventricular area
    Units: cm2
        arithmetic mean (standard deviation)
    14.51 ± 4.60
    ±
    ±
    Tricuspid annular plane systolic excursion
    Units: cm
        arithmetic mean (standard deviation)
    2.48 ± 0.47
    ±
    ±
    Forced Vital Capacity
    Units: percent
        arithmetic mean (standard deviation)
    69.84 ± 15.58
    ±
    ±
    Forced Expiratory Volume in 1 second
    Units: litre(s)
        arithmetic mean (standard deviation)
    2.33 ± 0.70
    ±
    ±
    FEV1 % Vital capacity max
    Units: percent
        arithmetic mean (standard deviation)
    80.38 ± 11.83
    ±
    ±
    PEF
    Units: litre/second
        arithmetic mean (standard deviation)
    5.31 ± 2.02
    ±
    ±
    Total lung capacity
    Units: litre(s)
        arithmetic mean (standard deviation)
    5.02 ± 1.15
    ±
    ±
    Residual volume
    Units: litre(s)
        arithmetic mean (standard deviation)
    2.06 ± 0.63
    ±
    ±
    Diffusion capacity of the lung
    Units: mmol/min/kPa
        arithmetic mean (standard deviation)
    5.16 ± 1.42
    ±
    ±
    Diffusion capacity of the lung percent predicted
    Units: percent
        arithmetic mean (standard deviation)
    84.45 ± 2.27
    ±
    ±
    SaO2
    Units: percent
        arithmetic mean (standard deviation)
    96.47 ± 1.41
    ±
    ±
    PaO2
    Units: mmHg
        arithmetic mean (standard deviation)
    80.00 ± 7.85
    ±
    ±
    PaCO2
    Units: mmHg
        arithmetic mean (standard deviation)
    38.12 ± 3.23
    ±
    ±
    Hemoglobin
    Units: g/dl
        arithmetic mean (standard deviation)
    13.58 ± 1.18
    ±
    ±
    Hematocrit
    Units: 1/l
        arithmetic mean (standard deviation)
    0.41 ± 0.03
    ±
    ±
    Platelet
    Units: 100/nl
        arithmetic mean (standard deviation)
    2.58 ± 0.79
    ±
    ±
    Creatinine
    Units: mg/dl
        arithmetic mean (standard deviation)
    0.85 ± 0.14
    ±
    ±
    Potassium
    Units: mmol/l
        arithmetic mean (standard deviation)
    4.12 ± 0.43
    ±
    ±
    AST
    Units: U/l
        arithmetic mean (standard deviation)
    21.95 ± 16.12
    ±
    ±
    ALT
    Units: U/l
        arithmetic mean (standard deviation)
    27.18 ± 18.87
    ±
    ±
    LDH
    Units: U/l
        arithmetic mean (standard deviation)
    197.58 ± 45,54
    ±
    ±
    CRP
    Units: mg/l
        arithmetic mean (standard deviation)
    5.23 ± 8.77
    ±
    ±
    NTproBNP
    Units: pg/ml
        arithmetic mean (standard deviation)
    193.68 ± 242.81
    ±
    ±
    Physical functioning (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    57.24 ± 26.50
    ±
    ±
    Physical role functioning (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    43.42 ± 40.97
    ±
    ±
    Bodily pain (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    55.89 ± 29.33
    ±
    ±
    General health perception
    Units: score
        arithmetic mean (standard deviation)
    48.08 ± 17.58
    ±
    ±
    Vitality (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    46.71 ± 20.24
    ±
    ±
    Social role functioning (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    66.26 ± 26.24
    ±
    ±
    Emotional role functioning (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    56.16 ± 46.58
    ±
    ±
    Mental health (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    62.00 ± 18.36
    ±
    ±
    Physical summation score (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    50.18 ± 23.19
    ±
    ±
    Mental summation score (SF-36 questionnaire)
    Units: score
        arithmetic mean (standard deviation)
    55.84 ± 21.55
    ±
    ±

    End points

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    End points reporting groups
    Reporting group title
    ambrisentan
    Reporting group description
    		 Ambrisentan once daily starting at 5 mg/die in the beginning of the study. Dosage was up-titrated to 10 mg/die after 1-4 weeks according to the physician’s and the patient’s estimation. Study medication was provided orally with or without food. Treatment effect was controlled at each study visit and the dose was adapted. The patient took one or two tablets of ambrisentan 5 mg once daily.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets with the same treatment regimen (once daily) as the verum therapy were provided. One pill a day were given. Treatment effect was controlled at each study visit and the sham dose was adapted. The patient took one or two tablets once daily.
    Reporting group title
    ambrisentan
    Reporting group description
    		 Ambrisentan once daily starting at 5 mg/die in the beginning of the study. Dosage was up-titrated to 10 mg/die after 1-4 weeks according to the physician’s and the patient’s estimation. Study medication was provided orally with or without food. Treatment effect was controlled at each study visit and the dose was adapted. The patient took one or two tablets of ambrisentan 5 mg once daily.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets with the same treatment regimen (once daily) as the verum therapy were provided. One pill a day were given. Treatment effect was controlled at each study visit and the sham dose was adapted. The patient took one or two tablets once daily.

    Subject analysis set title
    All patients randomised
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Includes all patients that were randomised into the study

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Efficacy analysis set of all patients who completed the study

    Subject analysis set title
    Ambrisentan
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Efficacy analysis of all patients who completed the study

    Primary: mean pulmonary arterial pressure

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    End point title
    		 mean pulmonary arterial pressure
    End point description
    End point type
    Primary
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.73 ± 3.59
    -1.0 ± 6.40
    Statistical analysis title
    		 t-test with unequal variances (Welch-Test)
    Comparison groups
    Placebo v Ambrisentan
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.884
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.09
         upper limit
    		 3.56

    Secondary: Cardiac index

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    End point title
    		 Cardiac index
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: l/min
        arithmetic mean (standard deviation)
    -0.31 ± 0.71
    0.66 ± 1.17
    Statistical analysis title
    		 T-test with unequal variances (Welch-test)
    Comparison groups
    Placebo v Ambrisentan
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 1.18

    Secondary: Pulmonary vascular resistance

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    End point title
    		 Pulmonary vascular resistance
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: Wood Units
        arithmetic mean (standard deviation)
    0.02 ± 0.76
    -0.59 ± 0.79
    Statistical analysis title
    		 T-test with unequal variances
    Comparison groups
    Placebo v Ambrisentan
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.25
         upper limit
    		 -0.17

    Secondary: 6-minute walking distance

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    End point title
    		 6-minute walking distance
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: meter
        arithmetic mean (standard deviation)
    -16.53 ± 77.21
    21.53 ± 34.6
    No statistical analyses for this end point

    Secondary: Diffusion capacity of the lung

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    End point title
    		 Diffusion capacity of the lung
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    13
    17
    Units: percent predicted
        arithmetic mean (standard deviation)
    -0.44 ± 1.84
    1.19 ± 1.81
    No statistical analyses for this end point

    Secondary: Hemoglobin

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    End point title
    		 Hemoglobin
    End point description
    End point type
    Secondary
    End point timeframe
    Change form baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: g/dl
        arithmetic mean (standard deviation)
    0.19 ± 0.68
    -0.59 ± 0.86
    No statistical analyses for this end point

    Secondary: NTproBNP

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    End point title
    		 NTproBNP
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    13
    16
    Units: pg/ml
        arithmetic mean (standard deviation)
    31.00 ± 85.83
    -15.63 ± 207.48
    No statistical analyses for this end point

    Other pre-specified: mean pulmonary arterial pressure at peak exercise

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    End point title
    		 mean pulmonary arterial pressure at peak exercise
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    13
    15
    Units: mmHg
        arithmetic mean (standard deviation)
    1.08 ± 7.39
    -0.73 ± 6.23
    No statistical analyses for this end point

    Other pre-specified: pulmonary arterial wedge pressure at peak exercise

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    End point title
    		 pulmonary arterial wedge pressure at peak exercise
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    13
    14
    Units: mmHg
        arithmetic mean (standard deviation)
    0.85 ± 6.3
    4.93 ± 6.52
    No statistical analyses for this end point

    Other pre-specified: Cardiac index at peak exercise

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    End point title
    		 Cardiac index at peak exercise
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    13
    15
    Units: l/min/m^2
        arithmetic mean (standard deviation)
    -0.45 ± 1.36
    0.70 ± 0.81
    Statistical analysis title
    		 t-test with unequal variances (Welch test)
    Comparison groups
    Ambrisentan v Placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 t-test, 2-sided
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 2

    Other pre-specified: Workload at peak exercise

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    End point title
    		 Workload at peak exercise
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change form baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    13
    15
    Units: watt
        arithmetic mean (standard deviation)
    1.92 ± 16.01
    5.00 ± 16.9
    No statistical analyses for this end point

    Other pre-specified: Heart rate at peak exercise

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    End point title
    		 Heart rate at peak exercise
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    13
    15
    Units: beats/min
        arithmetic mean (standard deviation)
    6.00 ± 18.74
    7.47 ± 12.01
    No statistical analyses for this end point

    Other pre-specified: Pulmonary vascular resistance at peak exercise

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    End point title
    		 Pulmonary vascular resistance at peak exercise
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    13
    14
    Units: Wood Units
        arithmetic mean (standard deviation)
    0.003 ± 0.34
    -0.84 ± 0.48
    No statistical analyses for this end point

    Other pre-specified: Total pulmonary resistance at peak exercise

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    End point title
    		 Total pulmonary resistance at peak exercise
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    13
    15
    Units: mmHg*min*l^-1
        arithmetic mean (standard deviation)
    0.16 ± 0.63
    -0.56 ± 0.48
    No statistical analyses for this end point

    Other pre-specified: Modified rodnan skin score

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    End point title
    		 Modified rodnan skin score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: Score
        arithmetic mean (standard deviation)
    0.73 ± 2.15
    0.24 ± 0.97
    No statistical analyses for this end point

    Other pre-specified: Physical functioning (SF-36 questionnaire)

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    End point title
    		 Physical functioning (SF-36 questionnaire)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: score
        arithmetic mean (standard deviation)
    -2.00 ± 25.20
    -7.65 ± 21.66
    No statistical analyses for this end point

    Other pre-specified: Physical role functioning (SF-36 questionnaire)

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    End point title
    		 Physical role functioning (SF-36 questionnaire)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: score
        arithmetic mean (standard deviation)
    13.33 ± 38.81
    -10.29 ± 42.44
    No statistical analyses for this end point

    Other pre-specified: Bodily Pain (SF-36 questionnaire)

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    End point title
    		 Bodily Pain (SF-36 questionnaire)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: score
        arithmetic mean (standard deviation)
    -2.47 ± 28.19
    -9.29 ± 23.87
    No statistical analyses for this end point

    Other pre-specified: General health perception (SF-36 questionnaire)

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    End point title
    		 General health perception (SF-36 questionnaire)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: score
        arithmetic mean (standard deviation)
    0.20 ± 19.39
    -2.71 ± 10.62
    No statistical analyses for this end point

    Other pre-specified: Vitality (SF-36 questionnaire)

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    End point title
    		 Vitality (SF-36 questionnaire)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: score
        arithmetic mean (standard deviation)
    -5.00 ± 16.37
    -3.53 ± 12.34
    No statistical analyses for this end point

    Other pre-specified: Social role functioning (SF-36 questionnaire)

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    End point title
    		 Social role functioning (SF-36 questionnaire)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: score
        arithmetic mean (standard deviation)
    0.87 ± 27.69
    -2.18 ± 19.21
    No statistical analyses for this end point

    Other pre-specified: Emotional role functioning (SF-36 questionnaire)

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    End point title
    		 Emotional role functioning (SF-36 questionnaire)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: score
        arithmetic mean (standard deviation)
    8.80 ± 49.68
    -9.82 ± 36.76
    No statistical analyses for this end point

    Other pre-specified: Mental health (SF-36 questionnaire)

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    End point title
    		 Mental health (SF-36 questionnaire)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: score
        arithmetic mean (standard deviation)
    -3.73 ± 11.85
    -4.47 ± 10.94
    No statistical analyses for this end point

    Other pre-specified: Physical summation score (SF-36 questionnaire)

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    End point title
    		 Physical summation score (SF-36 questionnaire)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: score
        arithmetic mean (standard deviation)
    0.87 ± 16.01
    -6.71 ± 12.17
    No statistical analyses for this end point

    Other pre-specified: Mental health score

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    End point title
    		 Mental health score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Placebo Ambrisentan
    Number of subjects analysed
    15
    17
    Units: score
        arithmetic mean (standard deviation)
    0.27 ± 19.77
    -4.65 ± 9.47
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline until 6 month visit + 30 days follow-up after last study drug intake
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Ambrisentan
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Ambrisentan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 19 (26.32%)
    1 / 19 (5.26%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphangitis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal infection
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lower jaw fracture
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Raynaud's phenomenon
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Ambrisentan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 19 (89.47%)
    17 / 19 (89.47%)
    Vascular disorders
    Dizziness
         subjects affected / exposed
    6 / 19 (31.58%)
    0 / 19 (0.00%)
         occurrences all number
    6
    0
    Hypotension
         subjects affected / exposed
    2 / 19 (10.53%)
    2 / 19 (10.53%)
         occurrences all number
    2
    2
    Epistaxis
         subjects affected / exposed
    1 / 19 (5.26%)
    3 / 19 (15.79%)
         occurrences all number
    1
    3
    Raynaud's phenomenon
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    3 / 19 (15.79%)
    1 / 19 (5.26%)
         occurrences all number
    3
    1
    Tachycardia
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 19 (31.58%)
    6 / 19 (31.58%)
         occurrences all number
    6
    6
    Paraesthesia
         subjects affected / exposed
    0 / 19 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    0
    4
    Tinnitus
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    edema
         subjects affected / exposed
    4 / 19 (21.05%)
    8 / 19 (42.11%)
         occurrences all number
    4
    8
    sweating
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Eye disorders
    Eye pain
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 19 (10.53%)
    4 / 19 (21.05%)
         occurrences all number
    2
    4
    Nausea
         subjects affected / exposed
    3 / 19 (15.79%)
    2 / 19 (10.53%)
         occurrences all number
    3
    2
    Gastrointestinal infection
         subjects affected / exposed
    3 / 19 (15.79%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Infection
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    Cough
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    Renal and urinary disorders
    Infection
    Additional description: urinary infection
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Rheumatic disorder
    Additional description: worsening of Underlying condition
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Oct 2015
    Change of site address due to relocation of main entrance of clinic
    29 Apr 2016
    Amendment 2 includes: • Clarification of exclusion criteria • Clarification of optional assessment of right atrial pressure by right heart catheterization during exercise • Change of packaging of the study drug (second batch of study drug was packed in modified blister sizes) • Change of the paragraph regarding the tear-off portions on the labels of study medication as labels with tear-off portions were not provided. • Adaptation of the timelines for the study according to the recruitment status and anticipated recruitment.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31655622
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