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    Clinical Trial Results:
    A double-blinded, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics, and acute cardiovascular responses of a 7-day oral treatment with the partial adenosine A1 receptor agonist BAY 1067197 in patients with chronic systolic heart failure: the PARSiFAL-pilot study

    Summary
    EudraCT number
    		 2013-002522-23
    Trial protocol
    		 DE   IT   NL  
    Global end of trial date
    02 Apr 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    08 Sep 2016
    First version publication date
    09 Apr 2016
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    • Correction of full data set
    Bayer sponsor contact information to be updated

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY1067197/16782
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02040233
    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
    02 Apr 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to investigate the safety and tolerability of a multiple dose 7-day once-daily (OD) BAY1067197 add-on treatment versus a 7-day add-on placebo treatment in subjects with chronic systolic heart failure (HF), determined by the incidence and severity of adverse events, newly-occurring laboratory and electrocardiogram (ECG) abnormalities and to investigate the pharmacokinetics (PK) of a 7-day BAY1067197 add-on treatment in subjects with chronic systolic HF.
    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 and/or their legally authorized representative 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
    28 Jan 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 1
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    24
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 6 centres in 4 countries, between 28 January 2014 (first subject, first visit) and 29 January 2015 (last subject, last visit).

    Pre-assignment
    Screening details
    		 Overall 61 subjects were screened, of them 25 were screen failure. The remaining 36 subjects were randomized to treatment, of them 5 were drop outs before study drug administration and 31 were assigned to treatment.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BAY1067197, 10 milligram (mg)
    Arm description
    		 Subjects received multiple oral doses of 10 mg of BAY1067197 tablet once daily (1 x 10 mg immediate-release [IR] tablet) for 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY1067197
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received multiple oral doses of BAY1067197 10mg (1x10 mg) tablet once daily for 7 days.

    Arm title
    		 BAY1067197, 20 mg
    Arm description
    		 Subjects received multiple oral doses of 20 mg BAY1067197 tablet once daily (2 x 10 mg IR tablet) for 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY1067197
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received multiple oral doses of 20 mg BAY1067197 tablet once daily (2 x 10 mg IR tablet) for 7 days.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received multiple oral doses of placebo matched to BAY1067197 tablet once daily for 7 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received multiple oral doses of placebo matched to BAY1067197 tablet once daily for 7 days.

    Number of subjects in period 1 [1]
    		BAY1067197, 10 milligram (mg) BAY1067197, 20 mg Placebo
    Started
    10
    11
    10
    Subjects received treatment
    10
    11
    10
    Fulfilled Requirements of FAS Population
    10
    11
    10
    Completed
    10
    11
    10
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Not all the enrolled subjects were treated with study drugs. As baseline only included treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BAY1067197, 10 milligram (mg)
    Reporting group description
    		 Subjects received multiple oral doses of 10 mg of BAY1067197 tablet once daily (1 x 10 mg immediate-release [IR] tablet) for 7 days.

    Reporting group title
    BAY1067197, 20 mg
    Reporting group description
    		 Subjects received multiple oral doses of 20 mg BAY1067197 tablet once daily (2 x 10 mg IR tablet) for 7 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received multiple oral doses of placebo matched to BAY1067197 tablet once daily for 7 days.

    Reporting group values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg Placebo Total
    Number of subjects
    		 10 11 10 31
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.8 ( 10.2 ) 56.9 ( 9.3 ) 57.8 ( 9.8 ) -
    Gender categorical
    Units: subjects
        Female
    		 3 4 0 7
        Male
    		 7 7 10 24

    End points

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    End points reporting groups
    Reporting group title
    BAY1067197, 10 milligram (mg)
    Reporting group description
    		 Subjects received multiple oral doses of 10 mg of BAY1067197 tablet once daily (1 x 10 mg immediate-release [IR] tablet) for 7 days.

    Reporting group title
    BAY1067197, 20 mg
    Reporting group description
    		 Subjects received multiple oral doses of 20 mg BAY1067197 tablet once daily (2 x 10 mg IR tablet) for 7 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received multiple oral doses of placebo matched to BAY1067197 tablet once daily for 7 days.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF (N=31) included subjects who received at least 1 dose of study drug.

    Subject analysis set title
    Pharmacokinetic (PK) analysis set (PKS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PKS (N=21) included subjects with at least 1 valid PK profile.

    Subject analysis set title
    Efficacy Analysis Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy analysis set (N=31) included subjects who had post-baseline efficacy data. Subjects with a major protocol deviation defined as no Cardiac Magnetic Resonance imaging (CMR) (Day 07d) and no echocardiography (Day 05d) were excluded from the efficacy evaluation.

    Subject analysis set title
    Pharmacodynamic (PD) analysis set (PDS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PDS (N=31) included subjects with at least 1 valid PD profile.

    Primary: Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Measured by Cardiac Magnetic Resonance Imaging (CMR) at Day 7

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    End point title
    		 Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Measured by Cardiac Magnetic Resonance Imaging (CMR) at Day 7 [1]
    End point description
    The change in LVEF between the post and the pre-treatment measurements were analyzed using Bayesian statistics to quantify the difference between BAY1067197 treatment and placebo measured by CMR. LVEF is the fraction of blood (in percent) pumped out of the heart’s left ventricular chamber with each heart beat, and is a measure of cardiac output for the heart.
    End point type
    Primary
    End point timeframe
    Baseline and Day 7
    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
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg Placebo
    Number of subjects analysed
    10 [2]
    11 [3]
    10 [4]
    Units: percentage of ejection fraction
    arithmetic mean (standard deviation)
        Baseline
    30.67 ( 10.52 )
    32.11 ( 7.64 )
    33.76 ( 9.88 )
        Change at Day 7
    0.12 ( 3.07 )
    2.15 ( 2.81 )
    1.77 ( 4.12 )
    Notes
    [2] - Efficacy analysis set
    [3] - Efficacy analysis set
    [4] - Efficacy analysis set
    No statistical analyses for this end point

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

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    End point title
    		 Maximum Observed Concentration of BAY84-3174 in Plasma (Cmax) After First Dose of BAY1067197 [5] [6]
    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
    Primary
    End point timeframe
    Day 1: pre-dose and 0.5, 1, 2, 3, 4, 6, 12 and 24 hours post-dose
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo-treated subjects (N=10) were excluded from the Pharmacokinetic analysis.
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg
    Number of subjects analysed
    10 [7]
    11 [8]
    Units: microgram per liter
        geometric mean (geometric coefficient of variation)
    31.2 ( 49.4 )
    55.1 ( 54.2 )
    Notes
    [7] - PKS
    [8] - PKS
    No statistical analyses for this end point

    Primary: Maximum Observed Concentration of BAY84-3174 in Plasma Divided by Dose (Cmax/D) After First Dose of BAY1067197

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    End point title
    		 Maximum Observed Concentration of BAY84-3174 in Plasma Divided by Dose (Cmax/D) After First Dose of BAY1067197 [9] [10]
    End point description
    Maximum observed drug concentration, directly taken from analytical data, divided by dose. Geometric mean and %CV were reported.
    End point type
    Primary
    End point timeframe
    Day 1: pre-dose and 0.5, 1, 2, 3, 4, 6, 12 and 24 hours post-dose
    Notes
    [9] - 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.
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo-treated subjects (N=10) were excluded from the Pharmacokinetic analysis.
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg
    Number of subjects analysed
    10 [11]
    11 [12]
    Units: 1 per liter*10^-3
        geometric mean (geometric coefficient of variation)
    3.9 ( 49.4 )
    3.44 ( 54.2 )
    Notes
    [11] - PKS
    [12] - PKS
    No statistical analyses for this end point

    Primary: Area Under the Concentration Versus Time Curve of BAY84-3174 for the Dosing Interval (AUCtau) After First Dose of BAY1067197

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    End point title
    		 Area Under the Concentration Versus Time Curve of BAY84-3174 for the Dosing Interval (AUCtau) After First Dose of BAY1067197 [13] [14]
    End point description
    AUCtau is defined as area under the plasma concentration time profile from time zero to the end of the dosing interval after the first dose and dosing interval was 24 h for both arms. Geometric mean and %CV were reported.
    End point type
    Primary
    End point timeframe
    Day 1: pre-dose and 0.5, 1, 2, 3, 4, 6, 12 and 24 hours post-dose
    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.
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo-treated subjects (N=10) were excluded from the Pharmacokinetic analysis.
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg
    Number of subjects analysed
    10 [15]
    11 [16]
    Units: microgram*hour per liter (mcg*h/L)
        geometric mean (geometric coefficient of variation)
    454 ( 42.5 )
    800 ( 47.4 )
    Notes
    [15] - PKS
    [16] - PKS
    No statistical analyses for this end point

    Primary: Area Under the Concentration Versus Time Curve of BAY84-3174 for the Dosing Interval Divided by Dose (AUCtau/D) After First Dose of BAY1067197

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    End point title
    		 Area Under the Concentration Versus Time Curve of BAY84-3174 for the Dosing Interval Divided by Dose (AUCtau/D) After First Dose of BAY1067197 [17] [18]
    End point description
    AUCtau/D is defined as area under the plasma concentration time profile from time zero to the end of the dosing interval divided by dose after the first dose and dosing interval was 24 h for both arms. Geometric mean and %CV were reported.
    End point type
    Primary
    End point timeframe
    Day 1: pre-dose and 0.5, 1, 2, 3, 4, 6, 12 and 24 hours post-dose
    Notes
    [17] - 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.
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo-treated subjects (N=10) were excluded from the Pharmacokinetic analysis.
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg
    Number of subjects analysed
    10 [19]
    11 [20]
    Units: hour per liter*10^-3
        geometric mean (geometric coefficient of variation)
    56.7 ( 42.5 )
    49.9 ( 47.4 )
    Notes
    [19] - PKS
    [20] - PKS
    No statistical analyses for this end point

    Primary: Maximum Observed Concentration of BAY84-3174 in Plasma (Cmax,md) After Multiple Dose Administration During a Dosing Interval

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    End point title
    		 Maximum Observed Concentration of BAY84-3174 in Plasma (Cmax,md) After Multiple Dose Administration During a Dosing Interval [21] [22]
    End point description
    Cmax,md is defined as maximum observed drug concentration in plasma after multiple-dose administrations during a dosing interval directly taken from analytical data.Geometric mean and %CV were reported.
    End point type
    Primary
    End point timeframe
    Day 7: pre dose and 0.5, 1, 2, 3, 4, 6 and 12 hours post dose; Day 8, Day 14, Day 22 and Day 29
    Notes
    [21] - 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.
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo-treated subjects (N=10) were excluded from the Pharmacokinetic analysis.
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg
    Number of subjects analysed
    10 [23]
    11 [24]
    Units: microgram per liter
        geometric mean (geometric coefficient of variation)
    66.3 ( 15.2 )
    120 ( 41.5 )
    Notes
    [23] - PKS
    [24] - PKS
    No statistical analyses for this end point

    Primary: Maximum Observed Concentration of BAY84-3174 in Plasma Divided by Dose (Cmax,md/D) After Multiple Dose Administration During a Dosing Interval

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    End point title
    		 Maximum Observed Concentration of BAY84-3174 in Plasma Divided by Dose (Cmax,md/D) After Multiple Dose Administration During a Dosing Interval [25] [26]
    End point description
    Maximum observed drug concentration, directly taken from analytical data divided by dose after multiple doses. Geometric mean and %CV were reported.
    End point type
    Primary
    End point timeframe
    Day 7: pre dose and 0.5, 1, 2, 3, 4, 6 and 12 hours post dose; Day 8, Day 14, Day 22 and Day 29
    Notes
    [25] - 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.
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo-treated subjects (N=10) were excluded from the Pharmacokinetic analysis.
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg
    Number of subjects analysed
    10 [27]
    11 [28]
    Units: one Per liter*10^-3
        geometric mean (geometric coefficient of variation)
    8.28 ( 15.2 )
    7.5 ( 41.5 )
    Notes
    [27] - PKS
    [28] - PKS
    No statistical analyses for this end point

    Primary: Area Under the Concentration Versus Time Curve of BAY84-3174 During any Dosing Interval (AUCtau,md) After Multiple Dose Administration

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    End point title
    		 Area Under the Concentration Versus Time Curve of BAY84-3174 During any Dosing Interval (AUCtau,md) After Multiple Dose Administration [29] [30]
    End point description
    AUCtau,md is defined as area under the plasma concentration time profile from time zero during the dosing interval after multiple-dose administrations and dosing interval was 24 h for both arms. Geometric mean and %CV were reported.
    End point type
    Primary
    End point timeframe
    Day 7: pre-dose and 0.5, 1, 2, 3, 4, 6, 12 and 24 hours post-dose
    Notes
    [29] - 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.
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo-treated subjects (N=10) were excluded from the Pharmacokinetic analysis.
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg
    Number of subjects analysed
    10 [31]
    11 [32]
    Units: microgram*hours per liter
        geometric mean (geometric coefficient of variation)
    1190 ( 14 )
    2030 ( 37.4 )
    Notes
    [31] - PKS
    [32] - PKS
    No statistical analyses for this end point

    Primary: Area Under the Concentration Versus Time Curve of BAY84-3174 During any Dosing Interval Divided by Dose (AUCtau,md/D) After Multiple Dose Administration

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    End point title
    		 Area Under the Concentration Versus Time Curve of BAY84-3174 During any Dosing Interval Divided by Dose (AUCtau,md/D) After Multiple Dose Administration [33] [34]
    End point description
    AUCtau,md/D is defined as area under the plasma concentration time profile from time zero to the end of the dosing interval after multiple dose of administrations divided by dose and dosing interval was 24 h for both arms. Geometric mean and %CV were reported.
    End point type
    Primary
    End point timeframe
    Day 7: pre-dose and 0.5, 1, 2, 3, 4, 6, 12 and 24 hours post-dose
    Notes
    [33] - 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.
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo-treated subjects (N=10) were excluded from the Pharmacokinetic analysis.
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg
    Number of subjects analysed
    10 [35]
    11 [36]
    Units: Hours per liter*10^-3
        geometric mean (geometric coefficient of variation)
    149 ( 14 )
    127 ( 37.4 )
    Notes
    [35] - PKS
    [36] - PKS
    No statistical analyses for this end point

    Primary: Number of Subjects With Relevant Changes in Heart Rate

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    End point title
    		 Number of Subjects With Relevant Changes in Heart Rate [37]
    End point description
    Heart rate was measured by monitor measurements after 30 minutes resting in a supine position. The relevant changes in heart rate were recorded and analysed.
    End point type
    Primary
    End point timeframe
    From the start of study treatment up to Day 29
    Notes
    [37] - 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
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg Placebo
    Number of subjects analysed
    10 [38]
    11 [39]
    10 [40]
    Units: subjects
    0
    0
    0
    Notes
    [38] - SAF
    [39] - SAF
    [40] - SAF
    No statistical analyses for this end point

    Primary: Number of Subjects With Relevant Changes in Blood Pressure

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    End point title
    		 Number of Subjects With Relevant Changes in Blood Pressure [41]
    End point description
    Blood pressure was measured by monitor measurements after 30 minutes resting in a supine position. The relevant changes in blood pressure were recorded and analysed.
    End point type
    Primary
    End point timeframe
    From the start of study treatment up to Day 29
    Notes
    [41] - 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
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg Placebo
    Number of subjects analysed
    10 [42]
    11 [43]
    10 [44]
    Units: subjects
    0
    0
    0
    Notes
    [42] - SAF
    [43] - SAF
    [44] - SAF
    No statistical analyses for this end point

    Primary: Number of Subjects With More than First Degree Atrio-Ventricular (AV) Block

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    End point title
    		 Number of Subjects With More than First Degree Atrio-Ventricular (AV) Block [45]
    End point description
    A complete standard 12-lead ECG was recorded and evaluated parameters such as heart rate, PR/PQinterval, QRSD interval, QT interval (uncorrected). Clinically relevant findings in ECG such as a second degree AV-block Mobitz type I (Wenkebach), Mobitz type II - or any third-degree AV block were recorded and reported. A 24-hour Holter ECG was recorded with a standard Holter ECG recorder for the purpose of detecting AV blocks, no higher degree AV blocks > 1 or clinically relevant effect on HR were observed during Holter monitoring periods.
    End point type
    Primary
    End point timeframe
    From the start of study treatment up to Day 29
    Notes
    [45] - 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
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg Placebo
    Number of subjects analysed
    10 [46]
    11 [47]
    10 [48]
    Units: subjects
        12-lead ECG
    0
    0
    0
        24-hour Holter ECG
    0
    0
    0
    Notes
    [46] - SAF
    [47] - SAF
    [48] - SAF
    No statistical analyses for this end point

    Secondary: Changes From Baseline for Wall Motion Score Index at Day (WMSI) as Measured by Cardiac Magnetic Resonance at Day 7

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    End point title
    		 Changes From Baseline for Wall Motion Score Index at Day (WMSI) as Measured by Cardiac Magnetic Resonance at Day 7
    End point description
    WMSI is evaluated using the American Heart Association (AHA) 17-segment model. The total WMS was obtained by adding the score for each segment. The WMSI was calculated by dividing the total WMS by 17. The wall motion score index was derived as the sum of all segmental scores divided by the number of segments visualized. In general, higher numbers are reflecting worsening cardiac function, normal function would be a wall motion score index of 1. Thus, range for the wall motion score index could be theoretically between 1 (normal) and 4. Thus, a decrease in wall motion score means improved function. Wall motion score index will cover the changes in wall motion score from baseline also.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 7
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg Placebo
    Number of subjects analysed
    10 [49]
    11 [50]
    10 [51]
    Units: scores on scale
    geometric mean (standard deviation)
        Baseline
    1.9 ( 0.584 )
    1.754 ( 0.548 )
    1.488 ( 0.678 )
        Change at Day 7
    -0.035 ( 0.084 )
    -0.118 ( 0.204 )
    -0.065 ( 0.217 )
    Notes
    [49] - Efficacy analysis set
    [50] - Efficacy analysis set
    [51] - Efficacy analysis set
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Relevant Changes Observed in Echocardiography Parameters

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    End point title
    		 Number of Subjects With Clinically Relevant Changes Observed in Echocardiography Parameters
    End point description
    The echo parameters like Septal mitral annulus (e’ septal), Lateral mitral annulus (e’ lateral), E/e’ average (average of e’ lateral and e’ septal), E/e’ Lateral ratio, E/e’ Septal ratio, Peak early doppler transmitral flow velocity (E), Peak atrial doppler transmitral flow velocity (A), E/A Ratio, Deceleration time (DT), Global longitudinal strain, Cardiac output, Stroke volume, Stroke volume index, Peak systolic tissue Doppler Velocity (Smax), Left ventricular end-systolic volume (LVESV), Left ventricular end-diastolic volume (LVEDV), Left atrial volume index (LAVI), Peak pulmonary systolic pressure (PAPsys) of which systolic and diastolic functions are measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 6 and 15
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg Placebo
    Number of subjects analysed
    10 [52]
    11 [53]
    10 [54]
    Units: Subjects
    0
    0
    0
    Notes
    [52] - Efficacy analysis set
    [53] - Efficacy analysis set
    [54] - Efficacy analysis set
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Relevant Changes Observed in Biomarkers

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    End point title
    		 Number of Subjects With Clinically Relevant Changes Observed in Biomarkers
    End point description
    N-terminal prohormone of brain natriuretic peptide (NT-proBNP), renin, mid-region pro-atrial natriuretic peptide (MR-proANP) are biomarkers which show effect on neurohormones.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 15
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg Placebo
    Number of subjects analysed
    10 [55]
    11 [56]
    10 [57]
    Units: subjects
    0
    0
    0
    Notes
    [55] - PDS
    [56] - PDS
    [57] - PDS
    No statistical analyses for this end point

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

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    End point title
    		 Time to Reach Maximum Observed Concentration of BAY84-3174 in Plasma (tmax) After First Dose of BAY1067197 [58]
    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
    Day 1: pre-dose and 0.5, 1, 2, 3, 4, 6, 12 and 24 hours post-dose
    Notes
    [58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo-treated subjects (N=10) were excluded from the Pharmacokinetic analysis.
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg
    Number of subjects analysed
    10 [59]
    11 [60]
    Units: hours
        median (full range (min-max))
    3.42 (2.92 to 4.08)
    4.05 (2.92 to 6.03)
    Notes
    [59] - PKS
    [60] - PKS
    No statistical analyses for this end point

    Secondary: Area Under the Concentration Versus Time Curve of BAY84-3174 for the Dosing Interval Divided by Dose per Body Weight (AUCtau,md,norm) After Multiple Dose Administration

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    End point title
    		 Area Under the Concentration Versus Time Curve of BAY84-3174 for the Dosing Interval Divided by Dose per Body Weight (AUCtau,md,norm) After Multiple Dose Administration [61]
    End point description
    AUCtau,md,norm is defined as area under the plasma concentration time profile from time zero to the end of the dosing interval after multiple dosing divided by dose per body weight. The dosing interval was 24 h for both arms. Geometric mean and %CV were reported.
    End point type
    Secondary
    End point timeframe
    Day 7: pre-dose and 0.5, 1, 2, 3, 4, 6, 12 and 24 hours post-dose
    Notes
    [61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo-treated subjects (N=10) were excluded from the Pharmacokinetic analysis.
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg
    Number of subjects analysed
    10 [62]
    11 [63]
    Units: kilogram* hour per liter
        geometric mean (geometric coefficient of variation)
    12.6 ( 15.9 )
    9.84 ( 37.9 )
    Notes
    [62] - PKS
    [63] - PKS
    No statistical analyses for this end point

    Secondary: Maximum Observed Concentration of BAY84-3174 in Plasma Divided by Dose per Body Weight (Cmax,md,norm) After Multiple Dose Administration

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    End point title
    		 Maximum Observed Concentration of BAY84-3174 in Plasma Divided by Dose per Body Weight (Cmax,md,norm) After Multiple Dose Administration [64]
    End point description
    Cmax,md,norm defined as maximum observed drug concentration in plasma after the first dose followed by multiple-dose administrations during a dosing interval divided by dose per body weight. Geometric mean and %CV were reported.
    End point type
    Secondary
    End point timeframe
    Day 7: pre dose and 0.5, 1, 2, 3, 4, 6 and 12 hours post dose; Day 8, Day 14, Day 22 and Day 29
    Notes
    [64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo-treated subjects (N=10) were excluded from the Pharmacokinetic analysis.
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg
    Number of subjects analysed
    10 [65]
    11 [66]
    Units: kilogram per liter
        geometric mean (geometric coefficient of variation)
    0.703 ( 16.2 )
    0.582 ( 38 )
    Notes
    [65] - PKS
    [66] - PKS
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Concentration of BAY84-3174 in Plasma (tmax,md) After Multiple Dose Administration

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    End point title
    		 Time to Reach Maximum Observed Concentration of BAY84-3174 in Plasma (tmax,md) After Multiple Dose Administration [67]
    End point description
    tmax,md defines as time to reach maximum drug concentration in the measured matrix after multiple dose administrations directly taken from analytical data.
    End point type
    Secondary
    End point timeframe
    Day 7: pre dose and 0.5, 1, 2, 3, 4, 6 and 12 hours post dose; Day 8, Day 14, Day 22 and Day 29
    Notes
    [67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo-treated subjects (N=10) were excluded from the Pharmacokinetic analysis.
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg
    Number of subjects analysed
    10 [68]
    11 [69]
    Units: hours
        median (full range (min-max))
    3.41 (2.08 to 6.08)
    4 (2.03 to 5.97)
    Notes
    [68] - PKS
    [69] - PKS
    No statistical analyses for this end point

    Secondary: Half-Life Associated With the Terminal Slope (t1/2,md) After Multiple-Dose Administration

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    End point title
    		 Half-Life Associated With the Terminal Slope (t1/2,md) After Multiple-Dose Administration [70]
    End point description
    t1/2,md is defiend as time to reach maximum observed drug concentration in plasma after the first dose followed by multiple-dose administrations. Geometric mean and %CV were reported.
    End point type
    Secondary
    End point timeframe
    Day 7: pre dose and 0.5, 1, 2, 3, 4, 6 and 12 hours post dose; Day 8, Day 14, Day 22 and Day 29
    Notes
    [70] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo-treated subjects (N=10) were excluded from the Pharmacokinetic analysis.
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg
    Number of subjects analysed
    10 [71]
    11 [72]
    Units: hours
        geometric mean (geometric coefficient of variation)
    307 ( 28.5 )
    312 ( 40.2 )
    Notes
    [71] - PKS
    [72] - PKS
    No statistical analyses for this end point

    Secondary: Maximum Observed Concentration of BAY84-3174 in Plasma After First Dose Divided by Dose per Body Weight (Cmax,norm)

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    End point title
    		 Maximum Observed Concentration of BAY84-3174 in Plasma After First Dose Divided by Dose per Body Weight (Cmax,norm) [73]
    End point description
    Cmax,norm is defined as maximum observed drug concentration in plasma after the first dose divided by dose per body weight. Geometric mean and %CV were reported.
    End point type
    Secondary
    End point timeframe
    Day 1: pre-dose and 0.5, 1, 2, 3, 4, 6, 12 and 24 hours post-dose
    Notes
    [73] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo-treated subjects (N=10) were excluded from the Pharmacokinetic analysis.
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg
    Number of subjects analysed
    10 [74]
    11 [75]
    Units: kilogram per liter
        geometric mean (geometric coefficient of variation)
    0.331 ( 36.5 )
    0.267 ( 55.6 )
    Notes
    [74] - PKS
    [75] - PKS
    No statistical analyses for this end point

    Secondary: Area Under the Concentration Versus Time Curve of BAY84-3174 for the Dosing Interval Divided by Dose per Body Weight (AUCtau,norm) After First Dose of BAY1067197

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    End point title
    		 Area Under the Concentration Versus Time Curve of BAY84-3174 for the Dosing Interval Divided by Dose per Body Weight (AUCtau,norm) After First Dose of BAY1067197 [76]
    End point description
    AUCtau,norm is defined as area under the plasma concentration time profile from time zero to the end of the dosing interval divided by dose per body weight after the first dose. Dosing interval was 24 h for both arms. Geometric mean and %CV were reported.
    End point type
    Secondary
    End point timeframe
    Day 1: pre-dose and 0.5, 1, 2, 3, 4, 6, 12 and 24 hours post-dose
    Notes
    [76] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Placebo-treated subjects (N=10) were excluded from the Pharmacokinetic analysis.
    End point values
    		 BAY1067197, 10 milligram (mg) BAY1067197, 20 mg
    Number of subjects analysed
    10 [77]
    11 [78]
    Units: kilogram*hour per liter
        geometric mean (geometric coefficient of variation)
    4.82 ( 31.7 )
    3.87 ( 54.9 )
    Notes
    [77] - PKS
    [78] - PKS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of study treatment up to 49 days after the last dose of study drug
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    BAY1067197, 10 mg
    Reporting group description
    		 Subjects received multiple oral doses of 10 mg of BAY1067197 tablet once daily (1 x 10 mg IR tablet) for 7 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received multiple oral doses of placebo tablet matched BAY1067197 once daily for 7 days.

    Reporting group title
    BAY1067197, 20 mg
    Reporting group description
    		 Subjects received multiple oral doses of 20 mg BAY1067197 tablet once daily (2 x 10 mg IR tablet) for 7 days.

    Serious adverse events
    		 BAY1067197, 10 mg Placebo BAY1067197, 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Ventricular tachycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 BAY1067197, 10 mg Placebo BAY1067197, 20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 10 (80.00%)
    4 / 10 (40.00%)
    8 / 11 (72.73%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Blood triglycerides increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 10 (10.00%)
    2 / 11 (18.18%)
         occurrences all number
    3
    2
    3
    Angina pectoris
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Sinus arrest
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Ventricular tachycardia
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 10 (30.00%)
    2 / 11 (18.18%)
         occurrences all number
    3
    4
    2
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Allergic oedema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Epigastric discomfort
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Nephropathy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Renal impairment
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Dec 2013
    Increase the lower limit for the HR at rest from 40 Beats Per Minute (BPM) to 50 (BPM) because of possible additive bradycardia-inducing effects of BAY1067197 in combination with metoprolol. Add an additional study visit on Day 21d. Exclude subjects with untreated hyperthyroidism or hypothyroidism and nonstable thyroid function (intake of stable thyroid hormone substitution was allowed).
    10 Mar 2014
    About 35 days after the last dose of BAY1067197, BAY84-3174 is largely eliminated from plasma, that is AUC at that time equals 96.875% of the total AUC consistent with the degree of elimination after 5 half-lives. Assuming a longer half-live in HF subjects compared to healthy subjects, an additional follow-up telephone contact was added on Day 49d (43 days after the last intake of study drug) for AE questioning. Hydroxybutyrate dehydrogenase (HBDH) and glutamate dehydrogenase (GLDH) were considered not relevant and excluded from the safety laboratory parameters.

    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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