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    Clinical Trial Results:
    An open-label phase IIIb study of riociguat in patients with in-operable CTEPH, or recurrent or persisting pulmonary hypertension (PH) after surgical treatment who are not satisfactorily treated and cannot participate in any other CTEPH trial

    Summary
    EudraCT number
    2012-002104-40
    Trial protocol
    SE   DE   PT   ES   BE   CZ   DK   NL   IT   AT   GB  
    Global end of trial date
    01 Dec 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Dec 2016
    First version publication date
    16 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY63-2521/16097
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01784562
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Dec 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objectives of this study were to assess safety and tolerability as well as clinical effects of riociguat treatment, and to provide access to riociguat for subjects with in-operable chronic thromboembolic pulmonary hypertension (CTEPH), or recurrent or persisting pulmonary hypertension (PH) after surgical treatment that were not satisfactorily treated and could not participate in any other CTEPH trial.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Mar 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
    Spain: 32
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    Turkey: 20
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    United States: 29
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Czech Republic: 11
    Country: Number of subjects enrolled
    Denmark: 13
    Country: Number of subjects enrolled
    France: 32
    Country: Number of subjects enrolled
    Germany: 62
    Country: Number of subjects enrolled
    Italy: 22
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    Mexico: 7
    Country: Number of subjects enrolled
    Netherlands: 19
    Country: Number of subjects enrolled
    Portugal: 9
    Country: Number of subjects enrolled
    Russian Federation: 4
    Worldwide total number of subjects
    300
    EEA total number of subjects
    227
    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)
    130
    From 65 to 84 years
    170
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study was conducted at 71 study centers in 19 countries, between 07 March 2013 (first subject first visit) and 01 December 2015 (last subject last visit).

    Pre-assignment
    Screening details
    Overall 315 subjects were screened, of them 15 were screen failures and 300 subjects were assigned to the treatment.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Riociguat up to 2.5 mg tid
    Arm description
    Subjects received riociguat film-coated tablets with starting dose of 1 milligram (mg) three times daily (tid). An individual riociguat dose was titrated every 2 weeks based on blood pressure titration rules and subject’s well-being. Dose modifications were done in 0.5 mg riociguat steps and the maximum dose was 2.5 mg tid.
    Arm type
    Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Adempas
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received riociguat film-coated tablets with starting dose of 1 mg tid. An individual riociguat dose was titrated every 2 weeks based on blood pressure titration rules and subject’s well-being. Dose modifications were done in 0.5 mg riociguat steps and the maximum dose was 2.5 mg tid.

    Number of subjects in period 1
    Riociguat up to 2.5 mg tid
    Started
    300
    Completed
    258
    Not completed
    42
         Physician decision
    5
         Screening failure
    1
         Consent withdrawn by subject
    7
         Protocol violation
    4
         Death
    5
         Adverse event
    15
         Lost to follow-up
    3
         Lack of efficacy
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Riociguat up to 2.5 mg tid
    Reporting group description
    Subjects received riociguat film-coated tablets with starting dose of 1 milligram (mg) three times daily (tid). An individual riociguat dose was titrated every 2 weeks based on blood pressure titration rules and subject’s well-being. Dose modifications were done in 0.5 mg riociguat steps and the maximum dose was 2.5 mg tid.

    Reporting group values
    Riociguat up to 2.5 mg tid Total
    Number of subjects
    300 300
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    130 130
        From 65-84 years
    170 170
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.9 ( 12.5 ) -
    Gender categorical
    Units: Subjects
        Female
    185 185
        Male
    115 115
    WHO Functional Class (FC)
    The WHO functional assessment of pulmonary arterial hypertension (PAH) ranged from functional class I (subjects with pulmonary hypertension [PH] but without resulting limitation of physical activity); class II (subjects with PH resulting in slight limitation of physical activity); class III (subjects with PH resulting in marked limitation of physical activity) to class IV (subjects with PH with inability to carry out any physical activity without symptoms). Changes to a lower WHO functional class resemble improvement; changes to a higher functional class resemble deterioration of PAH.
    Units: Subjects
        Class I
    5 5
        Class II
    112 112
        Class III
    175 175
        Class IV
    8 8
    6-Minute Walking Distance (6MWD) Test
    6MWD test (optional) was used to measure the subjects functional exercise capacity. 213 subjects performed the 6MWD test at baseline.
    Units: meter
        arithmetic mean (standard deviation)
    373.63 ( 117.02 ) -

    End points

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    End points reporting groups
    Reporting group title
    Riociguat up to 2.5 mg tid
    Reporting group description
    Subjects received riociguat film-coated tablets with starting dose of 1 milligram (mg) three times daily (tid). An individual riociguat dose was titrated every 2 weeks based on blood pressure titration rules and subject’s well-being. Dose modifications were done in 0.5 mg riociguat steps and the maximum dose was 2.5 mg tid.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    FAS (N=300) included all subjects who have been included in the study, were assigned to study treatment, and have received and taken at least 1 study drug administration.

    Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) [1]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; and another medically important serious event as judged by the investigator. Adverse events were considered to be treatment emergent if they had started or worsened after first administration of study medication up to 2 calendar days after end of treatment with study medication.
    End point type
    Primary
    End point timeframe
    Treatment-emergent AEs were collected from start of study treatment up to 2 days after the last drug intake
    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 were done, no inferential statistical analyses were performed.
    End point values
    Riociguat up to 2.5 mg tid
    Number of subjects analysed
    300 [2]
    Units: Subjects
        TEAE
    273
        TESAE
    89
    Notes
    [2] - FAS
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in the 6-Minute Walking Distance (6MWD) Test at Specified Timepoint

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    End point title
    Change From Baseline in the 6-Minute Walking Distance (6MWD) Test at Specified Timepoint
    End point description
    6MWD test were used to measure the subjects functional exercise capacity. The standardized walking course was 30 meters in length. This test was an optional assessment for ethical reasons, to open the early access of riociguat for subjects for as many subjects as possible, including subjects unable to walk and thus, unable to perform the walking test. Due to the optional nature data were not available for all the subjects and resulted in a large number of missing data. In the below table, "n" signifies the number of subjects who were evaluable for the specified category, respectively.
    End point type
    Other pre-specified
    End point timeframe
    Week 12 and Termination visit (after end of treatment which ranged from 2 days to 864 days)
    End point values
    Riociguat up to 2.5 mg tid
    Number of subjects analysed
    300 [3]
    Units: meter
    arithmetic mean (standard deviation)
        Week 12 (n=130)
    32.96 ( 42.33 )
        Termination Visit (n=105)
    36.95 ( 52.89 )
    Notes
    [3] - FAS
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline In World Health Organization (WHO) Functional Class at Specified Timepoint

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    End point title
    Change From Baseline In World Health Organization (WHO) Functional Class at Specified Timepoint
    End point description
    The WHO functional assessment of PAH ranged from functional class I (subjects with PH but without resulting limitation of physical activity); class II (subjects with PH resulting in slight limitation of physical activity); class III (subjects with PH resulting in marked limitation of physical activity) to class IV (subjects with PH with inability to carry out any physical activity without symptoms. These subjects manifest signs of right-heart failure). Changes to a lower WHO functional class resemble improvement; changes to a higher functional class resemble deterioration of PAH. In the below table, "n" signifies the number of subjects who were evaluable for the specified category, respectively.
    End point type
    Other pre-specified
    End point timeframe
    Week 12 and Termination visit (after end of treatment which ranged from 2 days to 864 days)
    End point values
    Riociguat up to 2.5 mg tid
    Number of subjects analysed
    300 [4]
    Units: percentage of subjects
    number (not applicable)
        Week 12; -2 (n= 264)
    0
        Week 12; -1 (n= 264)
    22
        Week 12; 0 (n= 264)
    73.1
        Week 12; 1 (n= 264)
    4.9
        Week 12; 2 (n= 264)
    0
        Termination Visit; -2 (n= 284)
    1.1
        Termination Visit; -1 (n= 284)
    23.9
        Termination Visit; 0 (n= 284)
    67.3
        Termination Visit; 1 (n= 284)
    7
        Termination Visit; 2 (n= 284)
    0.4
    Notes
    [4] - FAS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent AEs were collected from start of study treatment up to 2 days after the last drug intake
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Riociguat up to 2.5 mg tid
    Reporting group description
    Subjects received riociguat film-coated tablets with starting dose of 1 mg tid. An individual riociguat dose was titrated every 2 weeks based on blood pressure titration rules and subject’s well-being. Dose modifications were done in 0.5 mg riociguat steps and the maximum dose was 2.5 mg tid.

    Serious adverse events
    Riociguat up to 2.5 mg tid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    89 / 300 (29.67%)
         number of deaths (all causes)
    6
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine cancer
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colon neoplasm
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleomorphic malignant fibrous histiocytoma
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Colon cancer
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    4 / 300 (1.33%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Pulmonary artery therapeutic procedure
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    3 / 300 (1.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Postmenopausal haemorrhage
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    4 / 300 (1.33%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 300 (1.67%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Epistaxis
         subjects affected / exposed
    3 / 300 (1.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Lung disorder
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    3 / 300 (1.00%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Contusion
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Femur fracture
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    5 / 300 (1.67%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Atrial flutter
         subjects affected / exposed
    3 / 300 (1.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    8 / 300 (2.67%)
         occurrences causally related to treatment / all
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wolff-Parkinson-White syndrome
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac flutter
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleuropericarditis
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    17 / 300 (5.67%)
         occurrences causally related to treatment / all
    7 / 26
         deaths causally related to treatment / all
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 300 (1.67%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Loose tooth
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteitis
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    4 / 300 (1.33%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 300 (2.33%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Implant site infection
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Atypical mycobacterial pneumonia
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infected bite
         subjects affected / exposed
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Riociguat up to 2.5 mg tid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    234 / 300 (78.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    26 / 300 (8.67%)
         occurrences all number
    29
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    20 / 300 (6.67%)
         occurrences all number
    29
    Nervous system disorders
    Headache
         subjects affected / exposed
    54 / 300 (18.00%)
         occurrences all number
    78
    Dizziness
         subjects affected / exposed
    54 / 300 (18.00%)
         occurrences all number
    67
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    23 / 300 (7.67%)
         occurrences all number
    26
    Oedema peripheral
         subjects affected / exposed
    53 / 300 (17.67%)
         occurrences all number
    59
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    18 / 300 (6.00%)
         occurrences all number
    22
    Gastrooesophageal reflux disease
         subjects affected / exposed
    31 / 300 (10.33%)
         occurrences all number
    34
    Vomiting
         subjects affected / exposed
    34 / 300 (11.33%)
         occurrences all number
    44
    Nausea
         subjects affected / exposed
    43 / 300 (14.33%)
         occurrences all number
    50
    Dyspepsia
         subjects affected / exposed
    60 / 300 (20.00%)
         occurrences all number
    73
    Diarrhoea
         subjects affected / exposed
    45 / 300 (15.00%)
         occurrences all number
    53
    Constipation
         subjects affected / exposed
    31 / 300 (10.33%)
         occurrences all number
    36
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    22 / 300 (7.33%)
         occurrences all number
    29
    Dyspnoea
         subjects affected / exposed
    27 / 300 (9.00%)
         occurrences all number
    28
    Cough
         subjects affected / exposed
    38 / 300 (12.67%)
         occurrences all number
    44
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    17 / 300 (5.67%)
         occurrences all number
    19
    Back pain
         subjects affected / exposed
    20 / 300 (6.67%)
         occurrences all number
    20
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    31 / 300 (10.33%)
         occurrences all number
    39
    Bronchitis
         subjects affected / exposed
    17 / 300 (5.67%)
         occurrences all number
    20
    Urinary tract infection
         subjects affected / exposed
    16 / 300 (5.33%)
         occurrences all number
    18
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    16 / 300 (5.33%)
         occurrences all number
    17

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jul 2013
    Amendment included following changes: 1. The duration of treatment with riociguat during the study was limited to 18 months, starting when the first subject entered the study in the UK. 2. Timing of the diagnosis of CTEPH and the right heart catheter test prior to the study. 3. Option for urine pregnancy test (instead of serological test). 4. Timing of assessments relevant for titration (systolic blood pressure in relation to study medication intake). 5. Assessment criteria for subject operability.

    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.
    Clinical effects (6MWD, WHO FC) were recorded as primary endpoint; but planned and analysed as exploratory in accordance with protocol. Both reported as other pre-specified endpoint. Decimal places automatically truncated if last digit=0.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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