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    Clinical Trial Results:
    Evaluation of the pharmacodynamic effects of riociguat in subjects with pulmonary hypertension and heart failure with preserved ejection fraction in a randomized, double blind, placebo controlled, parallel group, multicenter study

    Summary
    EudraCT number
    		 2014-003055-60
    Trial protocol
    		 AT   DE  
    Global end of trial date
    30 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Aug 2022
    First version publication date
    26 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RIO-40400
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02744339
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University of Vienna
    Sponsor organisation address
    Spitalgasse 23, Vienna, Austria, 1090
    Public contact
    Study Team Prof. Bonderman and Prof. Kastner, Medical University of Vienna, 0043 140400 48560, theresa-marie.dachs@meduniwien.ac.at
    Scientific contact
    Study Team Prof. Bonderman and Prof. Kastner, Medical University of Vienna, 0043 140400 48560, theresa-marie.dachs@meduniwien.ac.at
    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
    11 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFpEF). To date, neither established heart failure therapies nor pulmonary vasodilators proved beneficial. The primary objective of this study was to evaluate the efficacy of continuous treatment with the oral soluble guanylate cyclase stimulator riociguat in subjects with symptomatic PH -HFpEF (LVEF ≥50%).
    Protection of trial subjects
    The present clinical trial was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Eligible subjects had to meet all inclusion criteria and none of the exclusion criteria. All subjects signed the informed consent form prior to enrolement and were informed, that withdrawal from the study was possible at any time for any reason. Subjects were closely monitored throughout the study treatment period and an independent data monitoring committee regularly reviewed safety data.
    Background therapy
    		 The dose regimen of the background treatment had to be stable for >30 days before randomization. Diuretic therapy had to be stable for ≥1 week. Patients in need of intravenous (i.v.) diuretics, inotropes or i.v. vasodilators ≤30 days before randomization were excluded. The intake of 1) Phosphodiesterase type 5 inhibitors, 2) Nitric oxide donors, e.g. nitrates, 3) Phosphodiesterase inhibitors, e.g. dipyridamole or theophylline, 4) Inotropes or i.v. vasodilators and 5) Prostacyclin analogs or endothelin receptor antagonists was not allowed during the pre-treatment and the treatment phases of this study. Patients who medically required such drugs were not included in this study. Patients who newly required such drugs during the study had to be withdrawn.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Nov 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 107
    Country: Number of subjects enrolled
    Germany: 7
    Worldwide total number of subjects
    114
    EEA total number of subjects
    114
    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)
    19
    From 65 to 84 years
    95
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluated the effect of riociguat in subjects with symptomatic pulmonary hypertension and heart failure with preserved ejection fraction. The study was conducted at 5 study centers across Germany and Austria between 17-Mar-2016 and 30-Sep-2020.

    Pre-assignment
    Screening details
    		 Only subjects who met all study inclusion and none of the exclusion criteria were eligible to enroll in this study. Withdrawal from the clinical trial was possible at any time for any reason. Of 118 subjects screened, 114 were considered eligible to enrole in the study and start study drug treatment. 88 patients completed the study.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Subjects, investigators, and anyone involved in trial conduct or analysis remained blinded with regard to the randomised treatment assignment up to database lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Riociguat
    Arm description
    		 Film-coated tablets of riociguat in doses of 0.5 mg, 1 mg, or 1.5 mg were administered orally three times daily (TID) for 26 weeks in subjects with pulmonary hypertension and heart failure with preserved ejection fraction. The study phase consisted of an eight-week (up-)titration phase followed by 18 weeks of fixed-dose treatment. Patients started with a dose of 0.5 mg riociguat TID and were (up-)titrated to doses of 1.0 and 1.5 mg TID.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    Other name
    Adempas® film-coated tablet
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Doses of 0.5, 1.0, or 1.5 mg (as per individual dose titration) three times daily, oral route of administration

    Arm title
    		 Placebo
    Arm description
    		 Film-coated tablets of placebo matching riociguat (identical and therefore indistinguishable) were administered orally three times daily for 26 weeks in subjects with pulmonary hypertension and heart failure with preserved ejection fraction.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated tablets of placebo matching riociguat were administered orally three times daily for 26 weeks.

    Number of subjects in period 1
    		Riociguat Placebo
    Started
    58
    56
    Completed
    40
    48
    Not completed
    18
    8
         Consent withdrawn by subject
    7
    2
         Diagnosis of AL-Amyloidosis
    1
    -
         Non-tolerable adverse event
    4
    -
         Serious adverse event (including death)
    4
    3
         Lowest dose not tolerated
    2
    -
         Adverse event of special interest
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Riociguat
    Reporting group description
    		 Film-coated tablets of riociguat in doses of 0.5 mg, 1 mg, or 1.5 mg were administered orally three times daily (TID) for 26 weeks in subjects with pulmonary hypertension and heart failure with preserved ejection fraction. The study phase consisted of an eight-week (up-)titration phase followed by 18 weeks of fixed-dose treatment. Patients started with a dose of 0.5 mg riociguat TID and were (up-)titrated to doses of 1.0 and 1.5 mg TID.

    Reporting group title
    Placebo
    Reporting group description
    		 Film-coated tablets of placebo matching riociguat (identical and therefore indistinguishable) were administered orally three times daily for 26 weeks in subjects with pulmonary hypertension and heart failure with preserved ejection fraction.

    Reporting group values
    		 Riociguat Placebo Total
    Number of subjects
    		 58 56 114
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 11 8 19
        From 65-84 years
    		 47 48 95
        85 years and over
    		 0 0 0
    Gender categorical
    Differentiation between male and female gender.
    Units: Subjects
        Female
    		 46 37 83
        Male
    		 12 19 31
    RACE
    Units: Subjects
        White
    		 57 56 113
        Other
    		 1 0 1
    Left ventricular ejection fraction
    Mean ± SD Left ventricular ejection fraction of patients included in the full analysis set (FAS). The FAS included all randomised patients who satisfied the major study entry criteria, had a valid measurement of the primary endpoint at baseline and had at least one valid post-baseline measure of efficacy at week eight or 26.
    Units: Percent
        arithmetic mean (standard deviation)
    		 61.0 ( 6.7 ) 60.1 ( 6.0 ) -
    Mean pulmonary artery pressure
    Mean ± SD pulmonary artery pressure of patients included in the full analysis set (FAS). The FAS included all randomised patients who satisfied the major study entry criteria, had a valid measurement of the primary endpoint at baseline and had at least one valid post-baseline measure of efficacy at week eight or 26.
    Units: mmHg
        arithmetic mean (standard deviation)
    		 36.3 ( 10.23 ) 35.9 ( 9.60 ) -
    Mean pulmonary artery wedge pressure
    Mean ± SD pulmonary artery wedge pressure of patients included in the full analysis set (FAS). The FAS included all randomised patients who satisfied the major study entry criteria, had a valid measurement of the primary endpoint at baseline and had at least one valid post-baseline measure of efficacy at week eight or 26.
    Units: mmHg
        arithmetic mean (standard deviation)
    		 20.3 ( 4.59 ) 21.2 ( 5.11 ) -
    Estimated glomerular filtration rate
    Calculated by the Modification of Diet in Renal Disease formula.
    Units: ml/min/1.73m^2
        arithmetic mean (standard deviation)
    		 63.4 ( 21.9 ) 61.7 ( 20.1 ) -
    Cardiac output
    Mean ± SD cardiac output of patients included in the full analysis set (FAS). The FAS included all randomised patients who satisfied the major study entry criteria, had a valid measurement of the primary endpoint at baseline and had at least one valid post-baseline measure of efficacy at week eight or 26)
    Units: L/min
        arithmetic mean (standard deviation)
    		 5.16 ( 1.131 ) 5.05 ( 1.494 ) -

    End points

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    End points reporting groups
    Reporting group title
    Riociguat
    Reporting group description
    		 Film-coated tablets of riociguat in doses of 0.5 mg, 1 mg, or 1.5 mg were administered orally three times daily (TID) for 26 weeks in subjects with pulmonary hypertension and heart failure with preserved ejection fraction. The study phase consisted of an eight-week (up-)titration phase followed by 18 weeks of fixed-dose treatment. Patients started with a dose of 0.5 mg riociguat TID and were (up-)titrated to doses of 1.0 and 1.5 mg TID.

    Reporting group title
    Placebo
    Reporting group description
    		 Film-coated tablets of placebo matching riociguat (identical and therefore indistinguishable) were administered orally three times daily for 26 weeks in subjects with pulmonary hypertension and heart failure with preserved ejection fraction.

    Primary: Cardiac output

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    End point title
    		 Cardiac output
    End point description
    The primary efficacy variable was the change in cardiac output (CO) at rest from baseline to week 26 of treatment, measured by right heart catheterization. CO average using thermodilution principles was calculated from three different measurements. In case of atrial fibrillation (AF), five measurements were performed and averaged.
    End point type
    Primary
    End point timeframe
    Change from baseline to week 26.
    End point values
    		 Riociguat Placebo
    Number of subjects analysed
    38
    48
    Units: L/min
        arithmetic mean (standard deviation)
    0.365 ( 1.263 )
    -0.105 ( 0.921 )
    Statistical analysis title
    		 Superiority of riociguat versus placebo
    Statistical analysis description
    H0: β1 ≤ β2 where β1 refers to the effect of riociguat and β2 to the effect of placebo.
    Comparison groups
    Riociguat v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0142
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    0.541
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.112
         upper limit
    		 0.971

    Secondary: Pulmonary artery wedge pressure

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    End point title
    		 Pulmonary artery wedge pressure
    End point description
    The change in pulmonary artery wedge pressure (PAWP) from baseline to week 26 of treatment, measured by right heart catheterization, was assessed as a secondary efficacy variable.
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 26.
    End point values
    		 Riociguat Placebo
    Number of subjects analysed
    39
    48
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.2 ( 6.74 )
    -0.4 ( 8.33 )
    Statistical analysis title
    		 Superiority of riociguat versus Placebo
    Statistical analysis description
    Analogous to the primary efficacy variable, all secondary variables were compared between treatment regimens using an analysis of covariance (ANCOVA) model with baseline value as covariate, centre, treatment regimen, and the interaction term of centre and treatment regimen as fixed effects (without adjustment for multiplicity). The primary comparison was a one-sided test at the 2·5% significance level for the difference in treatment effects between riociguat and placebo.
    Comparison groups
    Riociguat v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9601
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    0.084
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.239
         upper limit
    		 3.406

    Secondary: Transpulmonary pressure gradient

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    End point title
    		 Transpulmonary pressure gradient
    End point description
    The change in transpulmonary pressure gradient (TPG) from baseline to week 26 of treatment, measured by right heart catheterization, was assessed as a secondary efficacy variable. TPG was calculated as the difference between mean pulmonary artery pressure and pulmonary artery wedge pressure.
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 26.
    End point values
    		 Riociguat Placebo
    Number of subjects analysed
    39
    47
    Units: mmHg
        arithmetic mean (standard deviation)
    -2.5 ( 5.89 )
    0.0 ( 7.10 )
    Statistical analysis title
    		 Superiority of riociguat versus placebo
    Statistical analysis description
    Analogous to the primary efficacy variable, all secondary variables were compared between treatment regimens using an analysis of covariance (ANCOVA) model with baseline value as covariate, centre, treatment regimen, and the interaction term of centre and treatment regimen as fixed effects (without adjustment for multiplicity). The primary comparison was a one-sided test at the 2·5% significance level for the difference in treatment effects between riociguat and placebo.
    Comparison groups
    Riociguat v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0023
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -5.669
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.251
         upper limit
    		 -2.086

    Secondary: Pulmonary vascular resistance

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    End point title
    		 Pulmonary vascular resistance
    End point description
    The change in pulmonary vascular resistance (PVR) from baseline to week 26 of treatment was calculated as the difference between mean pulmonary artery pressure and pulmonary artery wedge pressure by, times 80 and devided by cardiac output (all parameters derived from right heart catheterization).
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 26.
    End point values
    		 Riociguat Placebo
    Number of subjects analysed
    38
    47
    Units: dyn.s.cm^-5
        arithmetic mean (standard deviation)
    -38.1 ( 126.8 )
    6.6 ( 137.7 )
    Statistical analysis title
    		 Superiority of riociguat versus placebo
    Statistical analysis description
    Analogous to the primary efficacy variable, all secondary variables were compared between treatment regimens using an analysis of covariance (ANCOVA) model with baseline value as covariate, centre, treatment regimen, and the interaction term of centre and treatment regimen as fixed effects (without adjustment for multiplicity). The primary comparison was a one-sided test at the 2·5% significance level for the difference in treatment effects between riociguat and placebo.
    Comparison groups
    Riociguat v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0068
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -108.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -186.89
         upper limit
    		 -30.86

    Secondary: Systemic vascular resistance

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    End point title
    		 Systemic vascular resistance
    End point description
    The change in systemic vascular resistance (SVR) from baseline to week 26 of treatment was assessed as a secondary efficacy variable. SVR was calculated as the difference between mean systemic arterial pressure and mean right atrial pressure, times 80 and devided by cardiac output (all parameters derived from right heart catheterization).
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 26.
    End point values
    		 Riociguat Placebo
    Number of subjects analysed
    33
    41
    Units: dyn.s.cm^-5
        arithmetic mean (standard deviation)
    -91.1 ( 500.0 )
    -54.9 ( 392.1 )
    Statistical analysis title
    		 Superiority of riociguat versus placebo
    Statistical analysis description
    Analogous to the primary efficacy variable, all secondary variables were compared between treatment regimens using an analysis of covariance (ANCOVA) model with baseline value as covariate, centre, treatment regimen, and the interaction term of centre and treatment regimen as fixed effects (without adjustment for multiplicity). The primary comparison was a one-sided test at the 2·5% significance level for the difference in treatment effects between riociguat and placebo.
    Comparison groups
    Riociguat v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5555
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -54.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -236.99
         upper limit
    		 128.44

    Secondary: Left atrial area

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    End point title
    		 Left atrial area
    End point description
    The change in left atrial area (LAA) from baseline to week 26 of treatment, measured by cardiac magnetic resonance imaging, was assessed as a secondary efficacy variable.
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 26.
    End point values
    		 Riociguat Placebo
    Number of subjects analysed
    14
    22
    Units: mm^2
        arithmetic mean (standard deviation)
    -86.4 ( 452.55 )
    -32.9 ( 712.00 )
    Statistical analysis title
    		 Superiority of riociguat versus placebo [1]
    Statistical analysis description
    Analogous to the primary efficacy variable, all continuous secondary variables were compared between treatment regimens using an analysis of covariance (ANCOVA) model with baseline value as covariate, centre, treatment regimen, and the interaction term of centre and treatment regimen as fixed effects (without adjustment for multiplicity). The primary comparison was a one-sided test at the 2·5% significance level for the difference in treatment effects between riociguat and placebo.
    Comparison groups
    Riociguat v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5068
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    166.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 -
    Notes
    [1] - A low or upper value for the confidence interval may be missing. Values for both the lower and upper limit are expected to be provided with a 2-sided confidence interval.
    Justification: n.a.

    Secondary: Right ventricular stroke volume

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    End point title
    		 Right ventricular stroke volume
    End point description
    The change in right ventricular stroke volume (RVSV) from baseline to week 26 of treatment, measured by cardiac magnetic resonance imaging, was assessed as a secondary efficacy variable.
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 26.
    End point values
    		 Riociguat Placebo
    Number of subjects analysed
    17
    24
    Units: mL
        arithmetic mean (standard deviation)
    -0.7 ( 18.45 )
    -6.3 ( 25.22 )
    Statistical analysis title
    		 Superiority of riociguat versus placebo [2]
    Statistical analysis description
    Analogous to the primary efficacy variable, all continuous secondary variables were compared between treatment regimens using an analysis of covariance (ANCOVA) model with baseline value as covariate, centre, treatment regimen, and the interaction term of centre and treatment regimen as fixed effects (without adjustment for multiplicity). The primary comparison was a one-sided test at the 2·5% significance level for the difference in treatment effects between riociguat and placebo.
    Comparison groups
    Riociguat v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8449
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    1.1035
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 -
    Notes
    [2] - A low or upper value for the confidence interval may be missing. Values for both the lower and upper limit are expected to be provided with a 2-sided confidence interval.
    Justification: n.a.

    Secondary: Right ventricular ejection fraction

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    End point title
    		 Right ventricular ejection fraction
    End point description
    The change in right ventricular ejection fraction (RVEF) from baseline to week 26 of treatment, measured by cardiac magnetic resonance imaging, was assessed as a secondary efficacy variable.
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 26.
    End point values
    		 Riociguat Placebo
    Number of subjects analysed
    17
    24
    Units: percent
        arithmetic mean (standard deviation)
    -3.16 ( 9.01 )
    -1.98 ( 8.42 )
    Statistical analysis title
    		 Superiority of riociguat versus placebo [3]
    Statistical analysis description
    Analogous to the primary efficacy variable, all continuous secondary variables were compared between treatment regimens using an analysis of covariance (ANCOVA) model with baseline value as covariate, centre, treatment regimen, and the interaction term of centre and treatment regimen as fixed effects (without adjustment for multiplicity). The primary comparison was a one-sided test at the 2·5% significance level for the difference in treatment effects between riociguat and placebo.
    Comparison groups
    Riociguat v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7272
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -0.8824
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 0
    Notes
    [3] - A low or upper value for the confidence interval may be missing. Values for both the lower and upper limit are expected to be provided with a 2-sided confidence interval.
    Justification: n.a.

    Secondary: N-terminal prohormone B-type natriuretic peptide

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    End point title
    		 N-terminal prohormone B-type natriuretic peptide
    End point description
    The change in serum levels of median N-terminal prohormone B-type natriuretic peptide (NT-proBNP) from baseline to week 26 of treatment was assessed as a secondary efficacy variable.
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 26.
    End point values
    		 Riociguat Placebo
    Number of subjects analysed
    36
    43
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    60.35 (-184.20 to 238.00)
    76.00 (-169.50 to 533.00)
    Statistical analysis title
    		 Superiority of riociguat versus placebo
    Statistical analysis description
    For the continuous, non-normally distributed secondary endpoint NT-proBNP, differences were assessed using the two-sample Wilcoxon rank-sum test at a two-sided 5% significance level.
    Comparison groups
    Riociguat v Placebo
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5647
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: World Health Organization functional class improvement

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    End point title
    		 World Health Organization functional class improvement
    End point description
    Changes concerning the World Health Organization (WHO) functional class improvement were analysed by dichotomising into the outcomes “improvement by at least one class” and “no improvement or worsening”.
    End point type
    Secondary
    End point timeframe
    Change from baseline to week 26.
    End point values
    		 Riociguat Placebo
    Number of subjects analysed
    44
    46
    Units: Subjects
    11
    10
    Statistical analysis title
    		 Superiority of riociguat versus placebo
    Statistical analysis description
    Changes concerning the WHO functional class were analysed by dichotomising into two outcomes “improvement by at least one class” and “no improvement or worsening”. Differences between treatment groups were assessed by Fisher´s exact test.
    Comparison groups
    Riociguat v Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.1567
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5507
         upper limit
    		 2.4294

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events occurring during the course of the clinical study (i.e. from signing the informed consent form to the observational phase) were collected, documented, and reported to the sponsor by the investigator.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Riociguat
    Reporting group description
    		 Film-coated tablets of riociguat in doses of 0.5 mg, 1 mg, or 1.5 mg were administered orally three times daily (TID) for 26 weeks in subjects with pulmonary hypertension and heart failure with preserved ejection fraction. The study phase consisted of an eight-week (up-)titration phase followed by 18 weeks of fixed-dose treatment. Patients started with a dose of 0.5 mg riociguat TID and were (up-)titrated to doses of 1.0 and 1.5 mg TID.

    Reporting group title
    Placebo
    Reporting group description
    		 Film-coated tablets of placebo matching riociguat (identical and therefore indistinguishable) were administered orally three times daily for 26 weeks in subjects with pulmonary hypertension and heart failure with preserved ejection fraction.

    Serious adverse events
    		 Riociguat Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 58 (34.48%)
    19 / 56 (33.93%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    1
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Arthrodesis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral revascularisation
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery angioplasty
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transurethral prostatectomy
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stent insertion
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoid operation
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac pacemaker insertion
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 58 (5.17%)
    6 / 56 (10.71%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 56 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mixed connective tissue disease
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Endocarditis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 56 (5.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound sepsis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 56 (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
    		 Riociguat Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 58 (93.10%)
    55 / 56 (98.21%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 58 (3.45%)
    4 / 56 (7.14%)
         occurrences all number
    2
    4
    Vascular disorders
    Hypotension
         subjects affected / exposed
    13 / 58 (22.41%)
    7 / 56 (12.50%)
         occurrences all number
    13
    7
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    3 / 58 (5.17%)
    4 / 56 (7.14%)
         occurrences all number
    3
    4
    Atrial fibrillation
         subjects affected / exposed
    4 / 58 (6.90%)
    2 / 56 (3.57%)
         occurrences all number
    4
    2
    Cardiac failure
         subjects affected / exposed
    3 / 58 (5.17%)
    8 / 56 (14.29%)
         occurrences all number
    3
    8
    Palpitations
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 56 (5.36%)
         occurrences all number
    2
    3
    Tachycardia
         subjects affected / exposed
    5 / 58 (8.62%)
    1 / 56 (1.79%)
         occurrences all number
    5
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 58 (8.62%)
    10 / 56 (17.86%)
         occurrences all number
    5
    10
    Headache
         subjects affected / exposed
    6 / 58 (10.34%)
    6 / 56 (10.71%)
         occurrences all number
    6
    6
    Syncope
         subjects affected / exposed
    4 / 58 (6.90%)
    2 / 56 (3.57%)
         occurrences all number
    4
    2
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 58 (3.45%)
    7 / 56 (12.50%)
         occurrences all number
    2
    7
    Fatigue
         subjects affected / exposed
    7 / 58 (12.07%)
    7 / 56 (12.50%)
         occurrences all number
    7
    7
    Oedema peripheral
         subjects affected / exposed
    17 / 58 (29.31%)
    17 / 56 (30.36%)
         occurrences all number
    17
    17
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    4 / 58 (6.90%)
    6 / 56 (10.71%)
         occurrences all number
    4
    6
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    5 / 58 (8.62%)
    3 / 56 (5.36%)
         occurrences all number
    5
    3
    Diarrhoea
         subjects affected / exposed
    5 / 58 (8.62%)
    6 / 56 (10.71%)
         occurrences all number
    5
    6
    Gastrooesophageal reflux disease
         subjects affected / exposed
    7 / 58 (12.07%)
    3 / 56 (5.36%)
         occurrences all number
    7
    3
    Nausea
         subjects affected / exposed
    5 / 58 (8.62%)
    4 / 56 (7.14%)
         occurrences all number
    5
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 58 (18.97%)
    7 / 56 (12.50%)
         occurrences all number
    11
    7
    Dyspnoea
         subjects affected / exposed
    15 / 58 (25.86%)
    12 / 56 (21.43%)
         occurrences all number
    15
    12
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 56 (5.36%)
         occurrences all number
    3
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 58 (10.34%)
    2 / 56 (3.57%)
         occurrences all number
    6
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 56 (5.36%)
         occurrences all number
    2
    3
    Nasopharyngitis
         subjects affected / exposed
    4 / 58 (6.90%)
    6 / 56 (10.71%)
         occurrences all number
    4
    6
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    5 / 58 (8.62%)
    5 / 56 (8.93%)
         occurrences all number
    5
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 May 2019
    Opening of a new study site in Graz/Austria.
    07 May 2020
    The sponsor’s medical expert for the present study was changed from Assoc. Prof. Priv.-Doz. Dr. Diana Bonderman to Ass.-Prof. Dr. Johannes Kastner.

    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.
    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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