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    Clinical Trial Results:
    A prospective, randomized, double blinded, crossover, two-treatment, two-sequence, short term pharmacokinetic, pharmacodynamic and tolerability, single centre study to compare AOP200704 vs. Esmolol in healthy subjects.

    Summary
    EudraCT number
    		 2010-023311-34
    Trial protocol
    		 CZ  
    Global end of trial date
    05 Dec 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Feb 2017
    First version publication date
    01 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CPA 368-10
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AOP Orphan Pharmaceuticals AG
    Sponsor organisation address
    Wilhelminenstrasse 91/II f, Vienna, Austria, 1160
    Public contact
    Dr. Michael Zörer, AOP Orphan Pharmaceuticals AG, 0043 1503724446, michael.zoerer@aoporphan.com
    Scientific contact
    Univ.-Doz. Dr. Günther Krumpl, MRN Medical Research Network GmbH, 0043 6765667804, g.krumpl@medresnet.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
    12 Jan 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Dec 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Dec 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the short-term pharmacokinetics, pharmacodynamics and tolerability of Landiolol compared with Esmolol in Caucasians
    Protection of trial subjects
    Subject’s cardiovascular status was assessed at screening, including 2D echo. Study subjects‘ confinement period lasted from at least 11 hours before until at least 8 hours after study drug administration. The volunteers staid lying in bed from the start of dobutamine infusion until 2 hours after the end of landiolol or esmolol infusion. Continuous ECG monitoring, regular assessments of vital signs and local tolerability were performed. The group of 16 subjects was divided into subgroups. Max. 3 subjects in each subgroup were administered the study drug sequentionally during one day. Administration of dobutamine in each of the following subjects started not earlier than after 30 minutes of study medication infusion of the previous subject, i.e. at time when the hemodynamic response of the previous subject to administered medication was known. A wash-out period of at least 2 days between doses in study cross-over periods was adhered to. Each subject completed an End-of-study examination within 72 hours after completion of Period 2.
    Background therapy
    		 Dobutamin ADMEDA 250 (Dobutamine hydrochloride 280 mg (corresponding to dobutamine 250 mg)) was administered intravenously. A dose of 10 µg/kg/min was administered for ten minutes, incrementing by 5 µg/kg/min for ten minutes until the requested heart rate increase by 30 bpm above baseline value or a maximum dose of 30 µg/kg/min was reached. The infusion at the target rate was maintained for another 20 minutes, then during and after the Test or Reference (T/R) infusion until the heart rate returned to value before T/R infusion or for 60 minutes after the end of T/R infusion at maximum.
    Evidence for comparator
    		 Esmolol, another short acting intravenous beta blocker registered since 2006 with a well known efficacy and safety profile was chosen as a comparator. Since the steady state effective doses of landiolol (10-40 µg/kg/min), and Esmolol (50-200 µg/kg/min) share a relation of 1:5 a dose of about 10 and 50 µg/kg/min was chosen for landiolol and esmolol.
    Actual start date of recruitment
    08 Mar 2011
    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
    Czech Republic: 16
    Worldwide total number of subjects
    16
    EEA total number of subjects
    16
    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)
    16
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 All 16 subjects met the inclusion criteria and were randomized.

    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
    Blinding implementation details
    The study was conducted as a double-blinded study. Pharmacist and the pump operator were the unblinded parties. These two, however, had no influence either on data collection or data capturing, reporting or evaluation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment sequence A
    Arm description
    		 Administration of AOP200704 in Period 1 (TEST treatment), administration of Esmolol in Period 2 (REFERENCE treatment).
    Arm type
    		 Experimental

    Investigational medicinal product name
    AOP200704
    Investigational medicinal product code
    CPA 368-10/T
    Other name
    Onoact® 50
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Test treatment - active ingredients: Landiolol hydrochloride. Dose: 10 µg/kg/min for 60 minutes. Infusion started 20 minutes after the effective dobutamine infusion rate had been started and was maintained for 60 minutes at the basic infusion rate if the basic infusion rate was effective. In case the heart rate was not reduced by 20 bpm or less within 40 minutes of the start of AOP200704 infusion at the basic rate, the rate of the infusion was planned to be doubled for the next 60 minutes.

    Investigational medicinal product name
    Esmolol
    Investigational medicinal product code
    CPA 368-10/R
    Other name
    Brevibloc
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Reference treatment. Dose: 50 µg/kg/min for 60 minutes. Infusion started 20 minutes after the effective dobutamine infusion rate had been started and was maintained for 60 minutes at the basic infusion rate if the basic infusion rate was effective. In case the heart rate was not reduced by 20 bpm or less within 40 minutes of the start of Esmolol infusion at the basic rate, the rate of the infusion was planned to be doubledfor the next 60 minutes.

    Arm title
    		 Treatment sequence B
    Arm description
    		 Administration of Esmolol in Period 1 (REFERENCE treatment), administration of AOP200704 in Period 2 (TEST treatment).
    Arm type
    		 Experimental

    Investigational medicinal product name
    AOP200704
    Investigational medicinal product code
    CPA 368-10/T
    Other name
    Onoact® 50
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Test treatment - active ingredients: Landiolol hydrochloride. Dose: 10 µg/kg/min for 60 minutes. Infusion started 20 minutes after the effective dobutamine infusion rate had been started and was maintained for 60 minutes at the basic infusion rate if the basic infusion rate was effective. In case the heart rate was not reduced by 20 bpm or less within 40 minutes of the start of AOP200704 infusion at the basic rate, the rate of the infusion was planned to be doubled for the next 60 minutes.

    Investigational medicinal product name
    Esmolol
    Investigational medicinal product code
    CPA 368-10/R
    Other name
    Brevibloc
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Reference treatment. Dose: 50 µg/kg/min for 60 minutes. Infusion started 20 minutes after the effective dobutamine infusion rate had been started and was maintained for 60 minutes at the basic infusion rate if the basic infusion rate was effective. In case the heart rate was not reduced by 20 bpm or less within 40 minutes of the start of Esmolol infusion at the basic rate, the rate of the infusion was planned to be doubled for the next 60 minutes.

    Number of subjects in period 1
    		Treatment sequence A Treatment sequence B
    Started
    8
    8
    Completed Period 1
    8
    8
    Started Period 2
    8
    8
    Completed
    8
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 16 16
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 16 16
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 33.1 ( 8.21 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 8 8
    Race
    Units: Subjects
        Caucasian
    		 16 16
    Smoking Habits
    Units: Subjects
        Non-smoker
    		 12 12
        Smoker
    		 4 4
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 75.9 ( 8.27 ) -
    Height
    Units: centimetre(s)
        arithmetic mean (standard deviation)
    		 176.9 ( 6.96 ) -
    BMI
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    		 24.16 ( 1.715 ) -
    Subject analysis sets

    Subject analysis set title
    Landiolol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Group intended for analysis of PK parameters of landiolol.

    Subject analysis set title
    Esmolol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Group intended for analysis of PK parameters of Esmolol.

    Subject analysis set title
    Pharmacodynamic (PD) Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Pharmacodynamic set consists of all subjects who completed the trial without violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the pharmacodynamic analysis. Subject with protocol deviation that could affect pharmacodynamic analysis was excluded from the Pharmacodynamic Set. The Pharmacodynamic Set was used for Pharmacodynamic analysis.

    Subject analysis set title
    AOP200704 (PD set)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Group intended for PD analysis of AOP200704.

    Subject analysis set title
    Esmolol (PD set)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Group intended for PD analysis of Esmolol.

    Subject analysis sets values
    		 Landiolol Esmolol Pharmacodynamic (PD) Set AOP200704 (PD set) Esmolol (PD set)
    Number of subjects
    16
    16
    15
    15
    15
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
    15
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    33.7 ( 8.2 )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    8
        Male
    7
    Race
    Units: Subjects
        Caucasian
    15
    Smoking Habits
    Units: Subjects
        Non-smoker
    11
        Smoker
    4
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    ( )
    ( )
    75.2 ( 8.04 )
    ( )
    ( )
    Height
    Units: centimetre(s)
        arithmetic mean (standard deviation)
    ( )
    ( )
    176.3 ( 6.65 )
    ( )
    ( )
    BMI
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    ( )
    ( )
    24.12 ( 1.769 )
    ( )
    ( )

    End points

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    End points reporting groups
    Reporting group title
    Treatment sequence A
    Reporting group description
    		 Administration of AOP200704 in Period 1 (TEST treatment), administration of Esmolol in Period 2 (REFERENCE treatment).

    Reporting group title
    Treatment sequence B
    Reporting group description
    		 Administration of Esmolol in Period 1 (REFERENCE treatment), administration of AOP200704 in Period 2 (TEST treatment).

    Subject analysis set title
    Landiolol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Group intended for analysis of PK parameters of landiolol.

    Subject analysis set title
    Esmolol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Group intended for analysis of PK parameters of Esmolol.

    Subject analysis set title
    Pharmacodynamic (PD) Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Pharmacodynamic set consists of all subjects who completed the trial without violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the pharmacodynamic analysis. Subject with protocol deviation that could affect pharmacodynamic analysis was excluded from the Pharmacodynamic Set. The Pharmacodynamic Set was used for Pharmacodynamic analysis.

    Subject analysis set title
    AOP200704 (PD set)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Group intended for PD analysis of AOP200704.

    Subject analysis set title
    Esmolol (PD set)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Group intended for PD analysis of Esmolol.

    Primary: Maximum plasma concentration - Cmax

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    End point title
    		 Maximum plasma concentration - Cmax
    End point description
    Maximum plasma concentration determined directly from the plasma concentration-time curve. (non-compartmental method)
    End point type
    Primary
    End point timeframe
    Plasma concentration measured during infusion up to 60 min and after end of infusion up to 480 min.
    End point values
    		 Landiolol Esmolol
    Number of subjects analysed
    16
    16
    Units: microgram(s)/millilitre
        geometric mean (standard deviation)
    0.188 ( 1.2028 )
    0.151 ( 1.486 )
    Statistical analysis title
    		 Ratio of geometric means
    Statistical analysis description
    Actual number of subjects due to crossover design: 16
    Comparison groups
    Landiolol v Esmolol
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.2472
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.067
         upper limit
    		 1.4579

    Primary: Time point of maximum plasma concentration - tmax

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    End point title
    		 Time point of maximum plasma concentration - tmax
    End point description
    Time point of maximum plasma concentration - tmax, determined directly from the plasma concentration-time curve. (non-compartmental method)
    End point type
    Primary
    End point timeframe
    Plasma concentration measured during infusion up to 60 min and after end of infusion up to 480 min.
    End point values
    		 Landiolol Esmolol
    Number of subjects analysed
    16
    16
    Units: minute
        median (full range (min-max))
    36 (12 to 60)
    19.8 (6 to 43.8)
    Statistical analysis title
    		 Median difference
    Comparison groups
    Landiolol v Esmolol
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    12
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 4.2
         upper limit
    		 21.9
    Notes
    [1] - Actual number of subjects due to crossover design: 16

    Primary: Terminal half-life - t1/2

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    End point title
    		 Terminal half-life - t1/2
    End point description
    Half-life of drug elimination during the terminal phase, estimated from the slope of linear regression of the semi-logarithmic plot of the terminal phase of the plasma concentration curve. (non-compartmental method)
    End point type
    Primary
    End point timeframe
    Plasma concentration measured during infusion up to 60 min and after end of infusion up to 480 min.
    End point values
    		 Landiolol Esmolol
    Number of subjects analysed
    16
    16
    Units: minute
        geometric mean (standard deviation)
    3.458 ( 1.1529 )
    2.846 ( 1.9225 )
    Statistical analysis title
    		 Ratio of geometric means
    Comparison groups
    Landiolol v Esmolol
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.2085
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.877
         upper limit
    		 1.6651
    Notes
    [2] - Actual number of subjects due to crossover design: 16

    Primary: Area under the plasma concentration-time curve - AUC(0-t)

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    End point title
    		 Area under the plasma concentration-time curve - AUC(0-t)
    End point description
    The area under the plasma concentration-time curve - AUC(0-t) was calculated by the linear trapezoidal rule from measured data points from time of administration until the time of last quantified concentration. (non-compartmental method)
    End point type
    Primary
    End point timeframe
    Plasma concentration measured during infusion up to 60 min and after end of infusion up to 480 min.
    End point values
    		 Landiolol Esmolol
    Number of subjects analysed
    16
    16
    Units: µg.h/mL
        geometric mean (standard deviation)
    0.16 ( 1.1752 )
    0.109 ( 1.4274 )
    Statistical analysis title
    		 Ratio of geometric means
    Comparison groups
    Esmolol v Landiolol
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.4709
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.2912
         upper limit
    		 1.6756
    Notes
    [3] - Actual number of subjects due to crossover design: 16

    Primary: Area under the plasma concentration-time curve - AUC(0-∞)

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    End point title
    		 Area under the plasma concentration-time curve - AUC(0-∞)
    End point description
    The area under the plasma concentration-time curve - AUC(0-∞) was be estimated by trapezoidal rule (AUC(0-t)) and extrapolation to infinity (AUC(t-∞)). (non-compartmental method)
    End point type
    Primary
    End point timeframe
    Plasma concentration measured during infusion up to 60 min and after end of infusion up to 480 min.
    End point values
    		 Landiolol Esmolol
    Number of subjects analysed
    16
    16
    Units: µg.h/mL
        geometric mean (standard deviation)
    0.162 ( 1.1734 )
    0.111 ( 1.4439 )
    Statistical analysis title
    		 Ratio of geometric means
    Comparison groups
    Landiolol v Esmolol
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.4651
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.2758
         upper limit
    		 1.6826
    Notes
    [4] - Actual number of subjects due to crossover design: 16

    Primary: Dose Necessary to Supress the Dobutamine induced HR increase

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    End point title
    		 Dose Necessary to Supress the Dobutamine induced HR increase
    End point description
    Dose [μg/kg] was calculated as 10 [μg/kg/min] x t [min] (for AOP200704) and 50 [μg/kg] x t [min] (for Esmolol), where t [min] is time needed to supress HR by 20 bpm after dobutamine induced HR increasing .
    End point type
    Primary
    End point timeframe
    From start of infusion to timetpoint of supressing HR by 20 bpm.
    End point values
    		 AOP200704 (PD set) Esmolol (PD set)
    Number of subjects analysed
    15
    15
    Units: microgram(s)/kilogram
        least squares mean (confidence interval 95%)
    66.34 (14.5 to 118.2)
    147.73 (94.6 to 200.9)
    Statistical analysis title
    		 Difference AOP - Esmolol
    Comparison groups
    AOP200704 (PD set) v Esmolol (PD set)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -81.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -154.6
         upper limit
    		 -8.2
    Notes
    [5] - Actual number of subjects due to crossover design: 15

    Primary: Dose/Efficacy Relation for the steady state condition

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    End point title
    		 Dose/Efficacy Relation for the steady state condition
    End point description
    Time to steady state was 60 min for all subjects. The following parameter was evaluated: Ratio [µg/kg/bpm] of dose [µg/kg] (administered during 60 min of IP infusion) and reduction of HR from baseline [bpm] at time of steady state conditions. This ratio presents the dose that is needed to be administered for the reduction of HR by 1 bpm (in steady state conditions).
    End point type
    Primary
    End point timeframe
    From start of infusion to time to steady state (4x half life) or 60 min.
    End point values
    		 AOP200704 (PD set) Esmolol (PD set)
    Number of subjects analysed
    15
    15
    Units: microgram(s)/kilogram/bpm
        least squares mean (confidence interval 95%)
    16.57 (5.24 to 27.91)
    95.55 (83.95 to 107.15)
    Statistical analysis title
    		 Difference AOP-Esmolol
    Comparison groups
    AOP200704 (PD set) v Esmolol (PD set)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -78.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -95.51
         upper limit
    		 -62.44
    Notes
    [6] - Actual number of subjects due to crossover design: 15

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    In each study period subjects were queried on adverse events at the admission to the clinical unit and at scheduled intervals till 8 hours after end of test or reference drug administration.
    Adverse event reporting additional description
    Moreover, the subjects were obliged to report immediately to the Investigator any adverse event, any other health related event that occured between signing the informed consent and the end-of-study examination.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14
    Reporting groups
    Reporting group title
    AOP200704
    Reporting group description
    		 Adverse events that occured during AOP200704 treatment period.

    Reporting group title
    Esmolol
    Reporting group description
    		 Adverse events that occured during Esmolol treatment period.

    Serious adverse events
    		 AOP200704 Esmolol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (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: 0.1%
    Non-serious adverse events
    		 AOP200704 Esmolol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 16 (43.75%)
    5 / 16 (31.25%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Ventricular extrasystoles
         subjects affected / exposed
    3 / 16 (18.75%)
    2 / 16 (12.50%)
         occurrences all number
    4
    2
    Ventricular tachycardia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 16 (6.25%)
         occurrences all number
    2
    1
    Paraesthesia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Feeling hot
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Piloerection
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Feb 2011
    PHAMOS Central & Eastern Europe s.r.o. was appointed as an organization in charge of study monitoring and ADDS s.r.o. as an organization responsible for data management and statistical evaluation. Corresponding sections of study protocol were modified as result of this Amendment 01.
    24 Oct 2011
    The results of the study showed unexpectedly short elimination of the reference drug esmolol both in pharmacokinetic and pharmacodynamic aspects. Amendment 02 to Study Protocol implements a simple pharmacokinetic branch studying esmolol pharmacokinetics under basal conditions (without dobutamine challenge) in three selected subjects of previous study group in order to obtain additional information for correct interpretation of the study results.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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