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    Clinical Trial Results:
    A single blind, placebo controlled pilot study to explore the safety and tolerability of a single oral dose of 30 mg BAY1067197 in patients with chronic heart failure on the background of preexisting beta-blocker therapy

    Summary
    EudraCT number
    2013-001287-34
    Trial protocol
    NL  
    Global end of trial date
    17 Mar 2015

    Results information
    Results version number
    v3(current)
    This version publication date
    15 Feb 2019
    First version publication date
    27 Mar 2016
    Other versions
    v1 , v2
    Version creation reason
    • Correction of full data set
    Control of data

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY1067197/16718
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01945606
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368, Leverkusen, Germany,
    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
    17 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this pilot study was to investigate the safety, tolerability and pharmacodynamic interaction of a single dose administration of 30 milligram (mg) BAY1067197 with selected beta-blockers in subjects with stable chronic systolic heart failure under evidence based standard therapy including selected beta-blockers.
    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 and/or their legally authorized representative. 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
    Subjects on stable standard therapy including pre-existing (for a minimum of 4 weeks) beta-blocker therapy.
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Nov 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
    Netherlands: 11
    Worldwide total number of subjects
    11
    EEA total number of subjects
    11
    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)
    7
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study was conducted at one study center in Netherlands, between 29 November 2013 (first subject first visit) and 09 September 2014 (last subject last visit).

    Pre-assignment
    Screening details
    Overall 14 subjects were screened, of them, 3 were screen failure and 11 were assigned to treatment.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject

    Arms
    Arm title
    Placebo then BAY1067197
    Arm description
    Subjects received single oral dose of placebo matched to BAY1067197 with selected standard betablocker therapy in fasted condition (treatment 1), and then followed by a single oral dose of 30 mg BAY1067197 tablet with selected standard betablocker therapy (either greater than or equal to [>=] 95 mg metoprolol succinate controlled release tablet, >=5 mg bisoprolol immediate release [IR] tablet or >=5 mg nebivolol IR tablet) in fasted condition (treatment 2).
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received single oral dose of placebo matched to BAY1067197 tablet on Day -1 in fasted condition.

    Investigational medicinal product name
    BAY1067197
    Investigational medicinal product code
    BAY1067197
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received single oral dose of 30mg BAY1067197 tablet on Day 0 in fasted condition.

    Investigational medicinal product name
    Beta-blockers
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received beta-blocker therapy with either >= 95mg metoprolol succinate (controlled release tablet) or >= 5mg bisoprolol (IR tablet) or >= 5mg nebivolol (IR tablet) with 30 mg BAY1067197 in treatment 2 and with placebo in treatment 1.

    Number of subjects in period 1
    Placebo then BAY1067197
    Started
    11
    Completed
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    Subjects received single oral dose of placebo matched to BAY1067197 with selected standard beta blocker therapy in fasted condition (treatment 1), and then followed by a single oral dose of 30 milligram (mg) BAY1067197 tablet with selected standard beta blocker therapy (either greater than or equal to [>=] 95 mg metoprolol succinate controlled release tablet, >=5 mg bisoprolol immediate release [IR] tablet or >=5 mg nebivolol IR tablet) in fasted condition (treatment 2).

    Reporting group values
    Overall Trial Total
    Number of subjects
    11
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    60.6 ( 7.3 ) -
    Gender Categorical
    Units: Subjects
        Male
    8 8
        Female
    3 3

    End points

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    End points reporting groups
    Reporting group title
    Placebo then BAY1067197
    Reporting group description
    Subjects received single oral dose of placebo matched to BAY1067197 with selected standard betablocker therapy in fasted condition (treatment 1), and then followed by a single oral dose of 30 mg BAY1067197 tablet with selected standard betablocker therapy (either greater than or equal to [>=] 95 mg metoprolol succinate controlled release tablet, >=5 mg bisoprolol immediate release [IR] tablet or >=5 mg nebivolol IR tablet) in fasted condition (treatment 2).

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    SAF (N=11) included all subjects who received at least one dose of the study medication.

    Subject analysis set title
    Pharmacodynamics (PD) analysis set (PDS)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PDS (N=11) included all subjects who completed the study without major changes versus protocol.

    Subject analysis set title
    Pharmacokinetics (PK) analysis set (PKS)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PKS (N=11) included all subjects who completed the study without major changes versus protocol.

    Subject analysis set title
    Placebo + Beta-blocker
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subject received a single oral dose of placebo matched to BAY1067197 under fasted condition (treatment 1) along with selected standard beta-blocker therapy (either >=95 mg metoprolol succinate controlled release tablet, >=5 mg bisoprolol IR tablet or >=5 mg nebivolol IR tablet).

    Subject analysis set title
    BAY1067197 30 mg + Beta-blocker
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received a single oral dose of 30 mg (3 X 10 mg) BAY1067197 tablet under fasted condition (treatment 2) along with selected standard beta-blocker therapy (either >=95 mg metoprolol succinate controlled release tablet, >=5 mg bisoprolol IR tablet or >=5 mg nebivolol IR tablet)

    Primary: Number of Subjects With Atrio-Ventricular (AV)-Block Greater than (>) one Degree (1^0) Under Therapy With BAY1067197 and Pre-existing Beta-blocker Therapy

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    End point title
    Number of Subjects With Atrio-Ventricular (AV)-Block Greater than (>) one Degree (1^0) Under Therapy With BAY1067197 and Pre-existing Beta-blocker Therapy [1]
    End point description
    A complete standard 12-lead ECG was recorded and evaluated parameters such as heart rate, PR/PQ interval, QRSD interval, QT interval (uncorrected). ECG finding AV block >1^0 were recorded and reported.
    End point type
    Primary
    End point timeframe
    From start of study drug administration until last follow-up (Day 22)
    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
    Placebo + Beta-blocker BAY1067197 30 mg + Beta-blocker
    Number of subjects analysed
    11 [2]
    11 [3]
    Units: Subjects
    0
    0
    Notes
    [2] - SAF
    [3] - SAF
    No statistical analyses for this end point

    Primary: Number of Subjects With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    Number of Subjects With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs) [4]
    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. Treatment-emergent were events between administration of study drug and up to Day 22 that were absent before treatment or that worsened relative to pre-treatment state.
    End point type
    Primary
    End point timeframe
    From start of study drug administration until last follow-up (Day 22)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Placebo + Beta-blocker BAY1067197 30 mg + Beta-blocker
    Number of subjects analysed
    11 [5]
    11 [6]
    Units: Subjects
        Treatment Emergent Adverse Event (TEAE)
    3
    7
        Treatment Emergent Serious Adverse Event (TESAE)
    0
    0
    Notes
    [5] - SAF
    [6] - SAF
    No statistical analyses for this end point

    Primary: Number of Subjects With Abnormal Laboratory Findings Reported as Treatment-emergent Adverse Events

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    End point title
    Number of Subjects With Abnormal Laboratory Findings Reported as Treatment-emergent Adverse Events [7]
    End point description
    Clinical laboratory examinations included hematology, clotting status, serum chemistry, virology, vasoactive hormones, bioanalytics and urinalysis. Abnormal laboratory parameters were reported as treatment-emergent adverse events. Treatment-emergent were events between administration of study drug and up to Day 22 that were absent before treatment or that worsened relative to pre-treatment state.
    End point type
    Primary
    End point timeframe
    From start of study drug administration until last follow-up (Day 22)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Placebo + Beta-blocker BAY1067197 30 mg + Beta-blocker
    Number of subjects analysed
    11 [8]
    11 [9]
    Units: Subjects
    0
    0
    Notes
    [8] - SAF
    [9] - SAF
    No statistical analyses for this end point

    Primary: Change From Baseline in Heart Rate at Specified Time Point

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    End point title
    Change From Baseline in Heart Rate at Specified Time Point [10]
    End point description
    Heart rate after resting in supine position for at least 30 minute was recorded and analysed. In the below table, "n" signifies subjects who were evaluable for the specified parameter for each arm, respectively. '99999' in the below table indicates that the data were not analysed for a respective reporting at specified time-points.
    End point type
    Primary
    End point timeframe
    From start of study drug administration until last follow-up (Day 22)
    Notes
    [10] - 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: EudraCT database does auto-addition of number of subjects analysed while reporting an explorative analysis of two treatment groups. Due to this format constraint, charts have been uploaded with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below.
    End point values
    Placebo + Beta-blocker BAY1067197 30 mg + Beta-blocker
    Number of subjects analysed
    11 [11]
    11 [12]
    Units: Beats/minutes
    arithmetic mean (standard deviation)
        Baseline, -1D 00H 00M
    62.5 ( 8.4 )
    99999 ( 99999 )
        Change at, -0D 23H 30M (n=11, 11)
    -2.5 ( 10.2 )
    99999 ( 99999 )
        Change at, -0D 23H 00M (n=11, 11)
    -3.1 ( 9.4 )
    99999 ( 99999 )
        Change at, -0D 22H 30M (n=11, 11)
    -4.8 ( 10.4 )
    99999 ( 99999 )
        Change at, -0D 22H 00M (n=11, 11)
    -3.3 ( 11.3 )
    99999 ( 99999 )
        Change at, -0D 21H 00M (n=11, 11)
    -4.5 ( 10.4 )
    99999 ( 99999 )
        Change at, -0D 20H 00M (n=11, 11)
    -4.3 ( 9.3 )
    99999 ( 99999 )
        Change at, -0D 18H 00M (n=11, 11)
    0.7 ( 10.4 )
    99999 ( 99999 )
        Change at, -0D 16H 00M (n=11, 11)
    -1.5 ( 10.3 )
    99999 ( 99999 )
        Change at, -0D 12H 00M (n=11, 11)
    -4.1 ( 9.5 )
    99999 ( 99999 )
        Baseline: 0D 00H 00M
    99999 ( 99999 )
    58.7 ( 5.6 )
        Change at, 0D 00H 30M (n=11, 11)
    99999 ( 99999 )
    -0.9 ( 2.3 )
        Change at, 0D 01H 00M (n=11, 11)
    99999 ( 99999 )
    -1.1 ( 4.2 )
        Change at, 0D 01H 30M (n=11, 11)
    99999 ( 99999 )
    -0.3 ( 5.4 )
        Change at, 0D 02H 00M (n=11, 11)
    99999 ( 99999 )
    -1.2 ( 4.5 )
        Change at, 0D 03H 00M (n=11, 11)
    99999 ( 99999 )
    -1.5 ( 4.9 )
        Change at, 0D 04H 00M (n=11, 11)
    99999 ( 99999 )
    -4.2 ( 3.6 )
        Change at, 0D 06H 00M (n=11, 11)
    99999 ( 99999 )
    1.7 ( 4 )
        Change at, 0D 08H 00M (n=11, 11)
    99999 ( 99999 )
    0.8 ( 4.4 )
        Change at, 0D 12H 00M (n=11, 11)
    99999 ( 99999 )
    -0.5 ( 3.5 )
        Change at, 1D 00H 00M (n=11, 11)
    99999 ( 99999 )
    0.5 ( 6.5 )
        Change at, 1D 06H 00M (n=11, 11)
    99999 ( 99999 )
    1.4 ( 3 )
        Change at, 1D 12H 00M (n=10, 10)
    99999 ( 99999 )
    5.2 ( 4.3 )
        Change at, 2D 00H 00M (n=11, 11)
    99999 ( 99999 )
    1.7 ( 5.2 )
        Change at, 5D 00H 00M (n=11, 11)
    99999 ( 99999 )
    2.5 ( 6.5 )
        Change at, 13D 00H 00M (n=11, 11)
    99999 ( 99999 )
    1.9 ( 5.3 )
    Attachments
    Statistical Analysis_Heart rate
    Notes
    [11] - SAF
    [12] - SAF
    No statistical analyses for this end point

    Primary: Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Findings

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    End point title
    Number of Subjects With Abnormal Clinically Significant Electrocardiogram (ECG) Findings [13]
    End point description
    A complete standard 12-lead ECG was recorded and evaluated parameters such as heart rate, PR/PQ interval, QRSD interval, QT interval (uncorrected). Criteria for abnormal clinically significant findings in the ECG were such as a second or third degree atrio-ventricular (AV) block. The changes in the above parameters were considered as "clinically significant" at the discretion of the investigator.
    End point type
    Primary
    End point timeframe
    From start of study drug administration until last follow-up (Day 22)
    Notes
    [13] - 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
    Placebo + Beta-blocker BAY1067197 30 mg + Beta-blocker
    Number of subjects analysed
    11 [14]
    11 [15]
    Units: Subjects
    0
    0
    Notes
    [14] - SAF
    [15] - SAF
    No statistical analyses for this end point

    Primary: Change From Baseline in Blood Pressure at Specified Time Point

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    End point title
    Change From Baseline in Blood Pressure at Specified Time Point [16]
    End point description
    Blood pressure measured by central bedside monitoring system to record subject’s Systolic blood pressure (SBP), Diastolic blood pressure (DBP) and mean arterial blood pressure (MAP). In the below table, "n" signifies subjects who were evaluable for the specified parameter for each arm, respectively. '99999' in the below table indicates that the data were not analysed for a respective reporting group at specified time-points.
    End point type
    Primary
    End point timeframe
    From start of study drug administration until last follow-up (Day 22)
    Notes
    [16] - 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: EudraCT database does auto-addition of number of subjects analysed while reporting an explorative analysis of two treatment groups. Due to this format constraint, charts have been uploaded with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below.
    End point values
    Placebo + Beta-blocker BAY1067197 30 mg + Beta-blocker
    Number of subjects analysed
    11 [17]
    11 [18]
    Units: Millimeters of mercury (mm of Hg)
    arithmetic mean (standard deviation)
        SBP: Baseline, -1D 00H 00M
    116.5 ( 15.7 )
    99999 ( 99999 )
        SBP: Change at, -0D 23H 30M
    6.8 ( 14.9 )
    99999 ( 99999 )
        SBP: Change at, -0D 23H 00M
    -0.5 ( 4.7 )
    99999 ( 99999 )
        SBP: Change at, -0D 22H 30M
    -0.9 ( 6.9 )
    99999 ( 99999 )
        SBP: Change at, -0D 22H 00M
    0.1 ( 8.2 )
    99999 ( 99999 )
        SBP: Change at, -0D 21H 00M
    -1.8 ( 8.1 )
    99999 ( 99999 )
        SBP: Change at, -0D 20H 00M
    -2.5 ( 8.3 )
    99999 ( 99999 )
        SBP: Change at, -0D 18H 00M
    -11.7 ( 10.8 )
    99999 ( 99999 )
        SBP: Change at, -0D 16H 00M
    -4.9 ( 5.4 )
    99999 ( 99999 )
        SBP: Change at, -0D 12H 00M
    -4.4 ( 11.6 )
    99999 ( 99999 )
        SBP: Baseline: 0D 00H 00M
    99999 ( 99999 )
    113.8 ( 16.5 )
        SBP: Change at, 0D 00H 30M
    99999 ( 99999 )
    1.2 ( 9.3 )
        SBP: Change at, 0D 01H 00M
    99999 ( 99999 )
    -0.8 ( 10.2 )
        SBP: Change at, 0D 01H 30M
    99999 ( 99999 )
    -1.9 ( 7.4 )
        SBP: Change at, 0D 02H 00M
    99999 ( 99999 )
    -0.4 ( 8 )
        SBP: Change at, 0D 03H 00M
    99999 ( 99999 )
    -2.6 ( 9.9 )
        SBP: Change at, 0D 04H 00M
    99999 ( 99999 )
    -2.6 ( 8.6 )
        SBP: Change at, 0D 06H 00M
    99999 ( 99999 )
    -11.4 ( 13.7 )
        SBP: Change at, 0D 08H 00M
    99999 ( 99999 )
    -6.4 ( 8.9 )
        SBP: Change at, 0D 12H 00M
    99999 ( 99999 )
    -0.5 ( 15.1 )
        SBP: Change at, 1D 00H 00M
    99999 ( 99999 )
    -1.3 ( 8.2 )
        SBP: Change at, 1D 06H 00M
    99999 ( 99999 )
    -5.5 ( 10.1 )
        SBP: Change at, 1D 12H 00M
    99999 ( 99999 )
    0.5 ( 8.9 )
        SBP: Change at, 2D 00H 00M
    99999 ( 99999 )
    6.1 ( 19.9 )
        SBP: Change at, 5D 00H 00M
    99999 ( 99999 )
    1.3 ( 10.9 )
        SBP: Change at, 13D 00H 00M
    99999 ( 99999 )
    -1 ( 13 )
        DBP: Baseline, -1D 00H 00M
    68.5 ( 14 )
    99999 ( 99999 )
        DBP: Change at, -0D 23H 30M
    5 ( 6.6 )
    99999 ( 99999 )
        DBP: Change at, -0D 23H 00M
    4.5 ( 6.5 )
    99999 ( 99999 )
        DBP: Change at, -0D 22H 30M
    -0.5 ( 11.1 )
    99999 ( 99999 )
        DBP: Change at, -0D 22H 00M
    3 ( 9.3 )
    99999 ( 99999 )
        DBP: Change at, -0D 21H 00M
    1 ( 7.3 )
    99999 ( 99999 )
        DBP: Change at, -0D 20H 00M
    1.2 ( 8.2 )
    99999 ( 99999 )
        DBP: Change at, -0D 18H 00M
    -5.5 ( 11.1 )
    99999 ( 99999 )
        DBP: Change at, -0D 16H 00M
    -5.4 ( 10.3 )
    99999 ( 99999 )
        DBP: Change at, -0D 12H 00M
    -2.5 ( 10.6 )
    99999 ( 99999 )
        DBP: Baseline: 0D 00H 00M
    99999 ( 99999 )
    70.5 ( 9.1 )
        DBP: Change at, 0D 00H 30M
    99999 ( 99999 )
    0.2 ( 9.7 )
        DBP: Change at, 0D 01H 00M
    99999 ( 99999 )
    -1.7 ( 12.2 )
        DBP: Change at, 0D 01H 30M
    99999 ( 99999 )
    -1.2 ( 8.8 )
        DBP: Change at, 0D 02H 00M
    99999 ( 99999 )
    -1.6 ( 9.9 )
        DBP: Change at, 0D 03H 00M
    99999 ( 99999 )
    -2.9 ( 7 )
        DBP: Change at, 0D 04H 00M
    99999 ( 99999 )
    -3.2 ( 8.9 )
        DBP: Change at, 0D 06H 00M
    99999 ( 99999 )
    -8.6 ( 9.8 )
        DBP: Change at, 0D 08H 00M
    99999 ( 99999 )
    -5.8 ( 8.3 )
        DBP: Change at, 0D 12H 00M
    99999 ( 99999 )
    -2.5 ( 7.1 )
        DBP: Change at, 1D 00H 00M
    99999 ( 99999 )
    0.6 ( 9 )
        DBP: Change at, 1D 06H 00M
    99999 ( 99999 )
    -5.4 ( 6.2 )
        DBP: Change at, 1D 12H 00M
    99999 ( 99999 )
    -5.9 ( 10.1 )
        DBP: Change at, 2D 00H 00M
    99999 ( 99999 )
    -1.4 ( 12.5 )
        DBP: Change at, 5D 00H 00M
    99999 ( 99999 )
    1.4 ( 10 )
        DBP: Change at, 13D 00H 00M
    99999 ( 99999 )
    0.6 ( 10 )
        MAP: Baseline, -1D 00H 00M
    84.485 ( 13.458 )
    99999 ( 99999 )
        MAP: Change at, -0D 23H 30M
    5.606 ( 6.933 )
    99999 ( 99999 )
        MAP: Change at, -0D 23H 00M
    2.879 ( 4.595 )
    99999 ( 99999 )
        MAP: Change at, -0D 22H 30M
    -0.606 ( 8.692 )
    99999 ( 99999 )
        MAP: Change at, -0D 22H 00M
    2.03 ( 7.162 )
    99999 ( 99999 )
        MAP: Change at, -0D 21H 00M
    0.061 ( 5.652 )
    99999 ( 99999 )
        MAP: Change at, -0D 20H 00M
    -0.061 ( 7.122 )
    99999 ( 99999 )
        MAP: Change at, -0D 18H 00M
    -7.545 ( 9.407 )
    99999 ( 99999 )
        MAP: Change at, -0D 16H 00M
    -5.212 ( 7.816 )
    99999 ( 99999 )
        MAP: Change at, -0D 12H 00M
    -3.091 ( 8.533 )
    99999 ( 99999 )
        MAP: Baseline: 0D 00H 00M
    99999 ( 99999 )
    84.97 ( 10.951 )
        MAP: Change at, 0D 00H 30M
    99999 ( 99999 )
    0.515 ( 8.957 )
        MAP: Change at, 0D 01H 00M
    99999 ( 99999 )
    -1.424 ( 11.084 )
        MAP: Change at, 0D 01H 30M
    99999 ( 99999 )
    -1.424 ( 7.553 )
        MAP: Change at, 0D 02H 00M
    99999 ( 99999 )
    -1.212 ( 8.737 )
        MAP: Change at, 0D 03H 00M
    99999 ( 99999 )
    -2.818 ( 7.732 )
        MAP: Change at, 0D 04H 00M
    99999 ( 99999 )
    -3 ( 8.388 )
        MAP: Change at, 0D 06H 00M
    99999 ( 99999 )
    -9.546 ( 10.276 )
        MAP: Change at, 0D 08H 00M
    99999 ( 99999 )
    -6 ( 8.024 )
        MAP: Change at, 0D 12H 00M
    99999 ( 99999 )
    -1.849 ( 9.521 )
        MAP: Change at, 1D 00H 00M
    99999 ( 99999 )
    0 ( 8.121 )
        MAP: Change at, 1D 06H 00M
    99999 ( 99999 )
    -5.394 ( 6.865 )
        MAP: Change at, 1D 12H 00M
    99999 ( 99999 )
    -3.788 ( 9.512 )
        MAP: Change at, 2D 00H 00M
    99999 ( 99999 )
    1.121 ( 13.942 )
        MAP: Change at, 5D 00H 00M
    99999 ( 99999 )
    1.333 ( 9.663 )
        MAP: Change at, 13D 00H 00M
    99999 ( 99999 )
    0.091 ( 10.005 )
    Attachments
    Statistical Analysis_Blood pressure
    Notes
    [17] - SAF
    [18] - SAF
    No statistical analyses for this end point

    Secondary: Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) of BAY84-3174 in Plasma After Single Dose of BAY1067197

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    End point title
    Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) of BAY84-3174 in Plasma After Single Dose of BAY1067197
    End point description
    Area under the concentration versus time curve from zero to infinity after single dose. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Secondary
    End point timeframe
    Pre-dose; 0 (0.5, 1, 2, 3, 4, 6 and 12 hours), 1, 2, 5, 13 and 21 days post-dose
    End point values
    BAY1067197 30 mg + Beta-blocker
    Number of subjects analysed
    11 [19]
    Units: microgram*hours per liter
        geometric mean (geometric coefficient of variation)
    4710.5 ( 45.21 )
    Notes
    [19] - PKS
    No statistical analyses for this end point

    Secondary: AUC of BAY84-3174 from Time 0 to the Last Data Point Greater than (>) Lower Limit of Quantification (AUC[0-last]) After Single Dose of BAY1067197

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    End point title
    AUC of BAY84-3174 from Time 0 to the Last Data Point Greater than (>) Lower Limit of Quantification (AUC[0-last]) After Single Dose of BAY1067197
    End point description
    AUC from time 0 to the last data point >lower limit of quantification, calculated up by linear trapezoidal rule, down by logarithmic trapezoidal rule. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Secondary
    End point timeframe
    Pre-dose; 0 (0.5, 1, 2, 3, 4, 6 and 12 hours), 1, 2, 5, 13 and 21 days post-dose
    End point values
    BAY1067197 30 mg + Beta-blocker
    Number of subjects analysed
    11 [20]
    Units: microgram*hours per liter
        geometric mean (geometric coefficient of variation)
    4046.8 ( 40.72 )
    Notes
    [20] - PKS
    No statistical analyses for this end point

    Secondary: Maximum Observed BAY84-3174 Concentration in Plasma (Cmax) After Single Dose of BAY1067197

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    End point title
    Maximum Observed BAY84-3174 Concentration in Plasma (Cmax) After Single Dose of BAY1067197
    End point description
    Maximum observed BAY84-3174 concentration in plasma, directly taken from analytical data. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Secondary
    End point timeframe
    Pre-dose; 0 (0.5, 1, 2, 3, 4, 6 and 12 hours), 1, 2, 5, 13 and 21 days post-dose
    End point values
    BAY1067197 30 mg + Beta-blocker
    Number of subjects analysed
    11 [21]
    Units: microgram per liter
        geometric mean (geometric coefficient of variation)
    95.159 ( 36.29 )
    Notes
    [21] - PKS
    No statistical analyses for this end point

    Secondary: Half-Life (t1/2) Associated With the Terminal Slope of BAY84-3174 After Single Dose of BAY1067197

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    End point title
    Half-Life (t1/2) Associated With the Terminal Slope of BAY84-3174 After Single Dose of BAY1067197
    End point description
    Half-life associated with the terminal slope. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Secondary
    End point timeframe
    Pre-dose; 0 (0.5, 1, 2, 3, 4, 6 and 12 hours), 1, 2, 5, 13 and 21 days post-dose
    End point values
    BAY1067197 30 mg + Beta-blocker
    Number of subjects analysed
    11 [22]
    Units: Hours
        geometric mean (geometric coefficient of variation)
    210.85 ( 17.77 )
    Notes
    [22] - PKS
    No statistical analyses for this end point

    Secondary: Apparent Oral Clearance (CL/F) of BAY84-3174 After Single Dose of BAY1067197

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    End point title
    Apparent Oral Clearance (CL/F) of BAY84-3174 After Single Dose of BAY1067197
    End point description
    Total body clearance of drug calculated after extra-vascular application.
    End point type
    Secondary
    End point timeframe
    Pre-dose; 0 (0.5, 1, 2, 3, 4, 6 and 12 hours), 1, 2, 5, 13 and 21 days post-dose
    End point values
    BAY1067197 30 mg + Beta-blocker
    Number of subjects analysed
    11 [23]
    Units: liter per hours
        geometric mean (geometric coefficient of variation)
    5.1013 ( 45.21 )
    Notes
    [23] - PKS
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum BAY84-3174 Concentration (tmax) in Plasma After Single Dose of BAY1067197

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    End point title
    Time to Reach Maximum BAY84-3174 Concentration (tmax) in Plasma After Single Dose of BAY1067197
    End point description
    Time to reach maximum drug concentration in the measured matrix, directly taken from analytical data.
    End point type
    Secondary
    End point timeframe
    Pre-dose; 0 (0.5, 1, 2, 3, 4, 6 and 12 hours), 1, 2, 5, 13 and 21 days post-dose
    End point values
    BAY1067197 30 mg + Beta-blocker
    Number of subjects analysed
    11 [24]
    Units: Hours
        median (full range (min-max))
    4 (1.83 to 4)
    Notes
    [24] - PKS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration until last follow-up (Day 22)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo + Beta-blocker
    Reporting group description
    Subject received a single oral dose of placebo under fasted condition (treatment 1) along with selected standard beta-blocker therapy (either >=95 mg metoprolol succinate controlled release tablet, >=5 mg bisoprolol IR tablet or >=5 mg nebivolol IR tablet).

    Reporting group title
    BAY1067197 30 mg + Beta-blocker
    Reporting group description
    Subjects received a single oral dose of 30 mg (3 X 10 mg) BAY1067197 tablet under fasted condition (treatment 2) along with selected standard beta-blocker therapy(either >=95 mg metoprolol succinate controlled release tablet, >=5 mg bisoprolol IR tablet or >=5 mg nebivolol IR tablet).

    Serious adverse events
    Placebo + Beta-blocker BAY1067197 30 mg + Beta-blocker
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo + Beta-blocker BAY1067197 30 mg + Beta-blocker
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 11 (27.27%)
    7 / 11 (63.64%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Implantable defibrillator replacement
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    2
    Headache
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 11 (9.09%)
         occurrences all number
    2
    1
    General disorders and administration site conditions
    Application site pruritus
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Paraesthesia oral
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Throat irritation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Oct 2013
    1. Status of the study was changed to pilot study 2. Deletion of leucine aminopeptidase as a laboratory parameter 3. Adverse events of special interest section was updated 4. Minor corrections to the protocol text.
    19 Nov 2013
    1. Exclusion of women of childbearing potential 2. Deletion of serum beta-human chorionic gonadotropin pregnancy test 3. Minor corrections to the protocol text.

    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.
    Occurrence of "±” in relation with geometric CV is auto-generated and cannot be deleted. Decimal places were automatically truncated if last decimal equals zero.
    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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