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    Clinical Trial Results:
    Open-label Two-arm PD and PK Study of Landiolol in Patients with Tachycardic Atrial Fibrillation or Atrial Flutter

    Summary
    EudraCT number
    		 2014-001905-42
    Trial protocol
    		 AT  
    Global end of trial date
    29 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Dec 2017
    First version publication date
    09 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LDLL600.201
    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/IIf, Vienna, Austria, A-1160
    Public contact
    Dr. Michael Zörer, AOP Orphan Pharmaceuticals AG, 0043 1503 72 44-46, michael.zoerer@aoporphan.com
    Scientific contact
    Univ.-Doz. Dr. Günther Krumpl, MRN Medical Research Network GmbH, 0043 6765 66 78 04, 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
    18 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To study pharmacodynamics of landiolol (LDLL600) in Caucasian patients with tachycardic atrial fibrillation (AF) or atrial flutter (AFL) treated either according to "alternative" or "conventional" dosing scheme
    Protection of trial subjects
    The Investigator obtained a written Informed Consent Form (ICF) from the patients before any screening procedures. Due to the acute clinical condition, exceptions were possible for screening safety laboratory parameters (within 24h). ECG and intravenous catheter insertion was routinely done before the start of the study. To ensure the safety of the patients continuous ECG and haemodynamic monitoring, and an assessment of local tolerability were performed during Landiolol infusion. Patients also completed an End-of-study examination 24 hours after Landiolol infusion discontinuation. The study was carried out in compliance with the principles of Good Clinical Practice (GCP) and the data protection regulation “Datenschutzgesetz 2000” (DSG 2000).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Nov 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
    Austria: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    9
    From 65 to 84 years
    10
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients presenting at the out-patient clinic or in-patients with tachycardic AF or AFL were asked to participate in this study.

    Pre-assignment
    Screening details
    		 Patients eligible for study participation and landiolol administration were enrolled into the study after giving their written informed consent. A total of 23 patients were screened and a total of 20 patients were enrolled and included.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Alternative treatment
    Arm description
    		 Patients treated with alternative dosing scheme.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Landiolol
    Investigational medicinal product code
    LDLL600
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Continuous infusion of 40 µg/kg/min (maximal total duration of 210 min).

    Arm title
    		 Conventional treatment
    Arm description
    		 Patients treated with conventional dosing scheme.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Landiolol
    Investigational medicinal product code
    LDLL600
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use , Intravenous drip use
    Dosage and administration details
    Bolus infusion of 100 µg/kg/min for one minute and then continuous infusion of 40 µg/kg/min (maximal total duration of 211 min).

    Number of subjects in period 1
    		Alternative treatment Conventional treatment
    Started
    10
    10
    Completed
    10
    9
    Not completed
    0
    1
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alternative treatment
    Reporting group description
    		 Patients treated with alternative dosing scheme.

    Reporting group title
    Conventional treatment
    Reporting group description
    		 Patients treated with conventional dosing scheme.

    Reporting group values
    		 Alternative treatment Conventional treatment Total
    Number of subjects
    		 10 10 20
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 5 4 9
        From 65-84 years
    		 5 5 10
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.9 ± 7 70.9 ± 9.9 -
    Gender categorical
    Units: Subjects
        Female
    		 2 6 8
        Male
    		 8 4 12
    Race
    Units: Subjects
        Caucasian
    		 10 10 20
    AF/AFL
    Units: Subjects
        AF
    		 9 8 17
        AFL
    		 1 2 3
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 27.31 ± 4.837 27.62 ± 3.257 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 182.7 ± 7.89 169.7 ± 10.7 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 91.2 ± 16.685 80.16 ± 15.923 -
    Pre-dose systolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 135.2 ± 20.7 139.3 ± 17.93 -
    Pre-dose heart rate
    Units: bpm
        arithmetic mean (standard deviation)
    		 125.8 ± 16.48 124.1 ± 13.68 -
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This set included all patients who received the investigational medicinal product. The evaluation of the primary endpoint - the successful control rate - and the evaluation of the secondary endpoints related to PD or dosing were assessed using this population set.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    This set included all patients who received the investigational medicinal product and was used for analysis of safety and tolerability data.

    Subject analysis set title
    Per-Protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This set included all treated patients without major protocol deviations and was used for analysis of PK and PD parameters.

    Subject analysis sets values
    		 Full Analysis Set Safety Set Per-Protocol set
    Number of subjects
    20
    20
    17
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    9
    9
    8
        From 65-84 years
    10
    10
    8
        85 years and over
    1
    1
    1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    67.4 ± 9.09
    67.4 ± 9.09
    67.2 ± 8.53
    Gender categorical
    Units: Subjects
        Female
    8
    8
    7
        Male
    12
    12
    10
    Race
    Units: Subjects
        Caucasian
    20
    20
    17
    AF/AFL
    Units: Subjects
        AF
    17
    17
    15
        AFL
    3
    3
    2
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    27.47 ± 4.016
    27.47 ± 4.016
    27.78 ± 4.09
    Height
    Units: cm
        arithmetic mean (standard deviation)
    176.2 ± 11.32
    176.2 ± 11.32
    175.9 ± 12.02
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    85.68 ± 16.854
    85.68 ± 16.854
    86.51 ± 18.024
    Pre-dose systolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    137.3 ± 18.97
    137.3 ± 18.97
    139 ± 17.67
    Pre-dose heart rate
    Units: bpm
        arithmetic mean (standard deviation)
    125 ± 14.77
    125 ± 14.77
    123 ± 15.2

    End points

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    End points reporting groups
    Reporting group title
    Alternative treatment
    Reporting group description
    		 Patients treated with alternative dosing scheme.

    Reporting group title
    Conventional treatment
    Reporting group description
    		 Patients treated with conventional dosing scheme.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This set included all patients who received the investigational medicinal product. The evaluation of the primary endpoint - the successful control rate - and the evaluation of the secondary endpoints related to PD or dosing were assessed using this population set.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    This set included all patients who received the investigational medicinal product and was used for analysis of safety and tolerability data.

    Subject analysis set title
    Per-Protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This set included all treated patients without major protocol deviations and was used for analysis of PK and PD parameters.

    Primary: Frequency of patients with successful HR control achieved and maintained during the first 16 min (including) after continuous landiolol infusion start

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    End point title
    		 Frequency of patients with successful HR control achieved and maintained during the first 16 min (including) after continuous landiolol infusion start
    End point description
    End point type
    Primary
    End point timeframe
    Period 1: Overall trial
    End point values
    		 Alternative treatment Conventional treatment Full Analysis Set
    Number of subjects analysed
    10
    10
    20
    Units: pts
        Successful HR control
    6
    4
    10
        Unsuccessful HR control
    4
    6
    10
    Statistical analysis title
    		 Comparison of groups
    Comparison groups
    Alternative treatment v Conventional treatment
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.6563
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [1] - Descriptive statistics, exploratory comparative tests.

    Secondary: Frequency of patients with successful HR control at any measurement time-point after continuous landiolol infusion start

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    End point title
    		 Frequency of patients with successful HR control at any measurement time-point after continuous landiolol infusion start
    End point description
    End point type
    Secondary
    End point timeframe
    Period 1: Overall Trial
    End point values
    		 Alternative treatment Conventional treatment Full Analysis Set
    Number of subjects analysed
    10
    10
    20
    Units: pts
        Successful HR control
    9
    4
    13
    Statistical analysis title
    		 Comparison of groups
    Comparison groups
    Alternative treatment v Conventional treatment
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.0573
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [2] - Descriptive statistics, exploratory comparative tests.

    Secondary: Frequency of patients with successful HR control achieved during the first 16 min (including) after continuous infusion start and maintained up to infusion end

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    End point title
    		 Frequency of patients with successful HR control achieved during the first 16 min (including) after continuous infusion start and maintained up to infusion end
    End point description
    End point type
    Secondary
    End point timeframe
    Period 1: Overall trial
    End point values
    		 Alternative treatment Conventional treatment Full Analysis Set
    Number of subjects analysed
    10
    10
    20
    Units: pts
        Successful HR control
    2
    2
    4
    Statistical analysis title
    		 Comparison of groups
    Comparison groups
    Alternative treatment v Conventional treatment
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [3] - Descriptive statistics, exploratory comparative tests.

    Secondary: Frequency of patients with successful HR control 60 min after continuous landiolol infusion end

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    End point title
    		 Frequency of patients with successful HR control 60 min after continuous landiolol infusion end
    End point description
    End point type
    Secondary
    End point timeframe
    Period 1: Overall trial
    End point values
    		 Alternative treatment Conventional treatment Full Analysis Set
    Number of subjects analysed
    10
    10
    20
    Units: pts
        Successful HR control
    4
    2
    6
    Statistical analysis title
    		 Comparison of groups
    Comparison groups
    Conventional treatment v Alternative treatment
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.3498
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [4] - Descriptive statistics, exploratory comparative tests.

    Secondary: Frequency of patients who converted to sinus rhythm evaluated at any measurement time point

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    End point title
    		 Frequency of patients who converted to sinus rhythm evaluated at any measurement time point
    End point description
    End point type
    Secondary
    End point timeframe
    Period 1: Overall trial
    End point values
    		 Alternative treatment Conventional treatment Full Analysis Set
    Number of subjects analysed
    10
    10
    20
    Units: pts
        Converted to sinus rhythm
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Time to successful HR control

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    End point title
    		 Time to successful HR control
    End point description
    Only patients with HR control included (N=13). The point estimate or limit of confidence interval was not possible to calculate in the “conventional” dosing scheme .
    End point type
    Secondary
    End point timeframe
    Period 1: Overall trial
    End point values
    		 Alternative treatment Conventional treatment Full Analysis Set
    Number of subjects analysed
    8
    0 [5]
    13
    Units: minute
        median (confidence interval 95%)
    12 (4 to 16)
    ( to )
    12 (4 to 16)
    Notes
    [5] - The point estimate and limit of confidence interval was not possible to calculate in this group.
    No statistical analyses for this end point

    Secondary: Time-points when dose adjustment or infusion discontinuation is requested and dose administered at this time-points

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    End point title
    		 Time-points when dose adjustment or infusion discontinuation is requested and dose administered at this time-points
    End point description
    Only data with dose change after landiolol infusion start were presented.
    End point type
    Secondary
    End point timeframe
    Period 1: Overall trial
    End point values
    		 Alternative treatment Conventional treatment Safety Set
    Number of subjects analysed
    10
    10
    20
    Units: pts
        4 min - Reduction: 20 µg/kg/min
    1
    0
    1
        8 min - Reduction: 20 µg/kg/min
    2
    0
    2
        16 min - Increase: 80 µg/kg/min
    3
    6
    9
        20 min - Increase: 100 µg/kg/min
    0
    1
    1
        30 min - Landiolol terminated
    3
    6
    9
        190 - Reduction: 10 µg/kg/min
    3
    0
    3
        190 min - Reduction: 20 µg/kg/min
    3
    3
    6
        190 min - Reduction: 40 µg/kg/min
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Average dose applied over course of the study

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    End point title
    		 Average dose applied over course of the study
    End point description
    End point type
    Secondary
    End point timeframe
    Period 1: Overall trial
    End point values
    		 Alternative treatment Conventional treatment Safety Set
    Number of subjects analysed
    10
    10
    20
    Units: µg/kg/min
    arithmetic mean (standard deviation)
        Average dose for individual patient
    40.7 ± 18.82
    56.4 ± 16.25
    48.5 ± 18.91
        Total dose for individual patient
    6149 ± 5579.96
    5498 ± 5765.82
    5823.5 ± 5532.41
    No statistical analyses for this end point

    Secondary: The frequency of patients with signs of local intolerability

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    End point title
    		 The frequency of patients with signs of local intolerability
    End point description
    End point type
    Secondary
    End point timeframe
    Period 1: Overall trial
    End point values
    		 Alternative treatment Conventional treatment Full Analysis Set
    Number of subjects analysed
    10
    10
    20
    Units: pts
        Erythema - 60 min, P : <=1 cm
    0
    1
    1
        Erythema - 60 min, P : Negative
    10
    9
    19
        Erythema - EOS : <= 1 cm
    0
    2
    2
        Erythema - EOS : Negative
    10
    7
    17
        Erythema - EOS : Not available
    0
    1
    1
        Pain - IMP end (30 min or 210 min) : Mild
    1
    0
    1
        Pain - IMP end (30 min or 210 min) : Negative
    9
    10
    19
    No statistical analyses for this end point

    Secondary: Total score of AF/AFL symptoms

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    End point title
    		 Total score of AF/AFL symptoms
    End point description
    The total score was calculated as sum of scores of the following individual symptoms: palpitations, irregular pulse, fatigue, rapid heartbeat, shortness of breath, dizziness and sweating. The overall score ranged between 0 and 7.
    End point type
    Secondary
    End point timeframe
    Period 1: Overall trial
    End point values
    		 Alternative treatment Conventional treatment Full Analysis Set
    Number of subjects analysed
    10
    10
    20
    Units: Score
    arithmetic mean (standard deviation)
        Pre-dose
    2.5 ± 2.42
    3.2 ± 1.32
    2.9 ± 1.93
        16 min
    1 ± 1.33
    0.6 ± 0.84
    0.8 ± 1.11
        30 min
    0.6 ± 1.13
    0.8 ± 0.96
    0.6 ± 1.03
        Landiolol end, 30 min
    1.7 ± 0.58
    0.5 ± 0.84
    0.9 ± 0.93
        Landiolol end, 210 min
    0.1 ± 0.38
    0.3 ± 0.5
    0.2 ± 0.4
        EOS
    1.1 ± 1.66
    1.1 ± 2.1
    1.1 ± 1.81
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameters of Landiolol

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    End point title
    		 Pharmacokinetic parameters of Landiolol
    End point description
    End point type
    Secondary
    End point timeframe
    Period 1: Overall trial
    End point values
    		 Per-Protocol set
    Number of subjects analysed
    17
    Units: µg/mL
    arithmetic mean (standard deviation)
        Cmax (µg/mL)
    1.717 ± 0.8676
        tmax (h)
    0.963 ± 1.0763
        Cmax (till HR success) (µg/mL)
    0.815 ± 0.5156
        AUC(0-t) (µg*h/mL)
    1.923 ± 1.4393
        AUC(0-t) (till HR success) (µg*h/mL)
    0.108 ± 0.1625
        λz (h^-1)
    8.693 ± 2.1835
        AUC(0-inf) (µg*h/mL)
    1.926 ± 1.439
        Residual area (%)
    0.24 ± 0.261
        t1/2 (min)
    5.042 ± 1.1464
        Total body clearance (CL) [mL/(kg*h)]
    2431.5 ± 805.623
        Volume of distribution (Vd) [mL/kg]
    289.86 ± 118.383
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing the informed consent form until follow-up visit.
    Adverse event reporting additional description
    Check for adverse events was performed during IMP infusion, 60 min after IMP infusion end and on End-of-Study visit (1 day after IMP infusion).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Alternative dosing scheme
    Reporting group description
    		 Subjects starting with 40 µg/kg/min continuous infusion.

    Reporting group title
    Concentional dosing scheme
    Reporting group description
    		 Subjects starting with one minute of 100 µg/kg/min bolus infusion and continuing with 40 µg/kg/min continuous infusion.

    Serious adverse events
    		 Alternative dosing scheme Concentional dosing scheme
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (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
    		 Alternative dosing scheme Concentional dosing scheme
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 10 (50.00%)
    4 / 10 (40.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Hypertension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Hypotension
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    Injection site pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         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
    10 Sep 2014
    The inclusion criterion n°2 (SBP ≥ 95 mmHg) was changed into SBP ≥ 100 mmHg. Correspondingly, the exclusion criterion n°1 (SBP ˂ 95 mmHg) was changed into SBP ˂ 100 mmHg.
    28 Jan 2015
    The exclusion criteria n°9 (Any ivabradine, antiarrhythmic and/or calcium channel blocker within the last 12h) and n°10 (Amiodarone therapy within the last 4 weeks) were suppressed. The blood sampling for amiodarone serum level assessment was added for patients pre-treated with amiodarone any time prior to first dose of landiolol. Concomitant medications were allowed except for ivabradine, amiodarone and/or calcium channel blocker administration “during investigational medicinal product infusion duration”. Then, subgroup or sensitivity analysis was planned to assess the effect of ivabradine, amiodarone and/or calcium channel blocker on PD/PK evaluation and safety.
    24 Jun 2015
    An additional arm was implemented (“conventional treatment arm”: one min of 100 µg/kg/min bolus infusion before switching to continuous infusion scheme with a dosing of 40 µg/kg/min). Then, the title of the study was modified: the “single-arm study” became the “two-arm” study as in the body of the Protocol. The term “monocentre” was deleted. The schedule of activities and regular dosing scheme during treatment were changed. The design of the study included now a pilot phase and a planned randomized phase. In the pilot phase, the first set of patients was to be treated with the “alternative dosing scheme” (40 µg/kg/min continuous infusion). Thereafter, the patients were to be treated with the “conventional dosing scheme”. Then, the patients were to be allocated to one of the two study arms in ratio 1:1. Depending on achievement of successful heart rate control, the dose was maintained, increased or reduced (according to the updated regular dosing scheme in appendix 3). The planned maximal continuous infusion duration was 180 min plus 30 min switch phase to oral therapy (210 min in total). Patients treated with “conventional” dosing scheme received a bolus infusion for one minute upfront resulting in 211 min total landiolol infusion. The dosing scheme was simplified: no mandatory dose reductions up to minute 16 and the sampling time point at minute 2 was deleted. In the same way, LTA was done at baseline, at the end of infusion, 60 min after the end of infusion and at follow-up visit. The primary objective was now to study PD of landiolol in Caucasian patients with tachycardic AF or AFL treated either according to the “alternative” or the “conventional” dosing scheme. The secondary objectives were now to study PK, tolerability and safety of the “alternative” and “conventional” landiolol dosing scheme in those patients. The study endpoints were changed accordingly. Enrolment duration changed to 15 months. Statistical methods were performed by study arms.
    28 Aug 2015
    An additional site was nominated (Prof. Lueger, Graz). Some laboratory parameters were removed from the schedule of assessments (prothrombine time [PT, INR, including PT-ratio], aPTT-ratio, cholesterol, total protein and albumin). The time points 45, 75, 90 and 150 min were added (including HR, ECG, BP, AE checks)

    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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